Study centres

Four TLM (The Leprosy Mission) centres participated in this study: The Leprosy Mission Community Hospital, Shahdara, New Delhi; The Leprosy Mission Hospital, Faizabad, Uttar Pradesh; The Leprosy Mission Hospital Champa, Chattisgarh; and Purulia Leprosy Home and Hospital, West Bengal. The trial started in Aug 2007 and finished in 2012.

Intervention

All patients received a 20 week course of prednisolone (P) as follows: P was started at a dose of 40 mg per day and reduced by 5 mg/day every two weeks till a dose of 20 mg/day was reached; 20 mg/day was given for four weeks, then 15 mg/day for four weeks. After this 10 mg/day P was given for two weeks and 5 mg/day for two weeks, (40x2, 35x2, 30x2, 25x2, 20x4, 15x4, 10x2 and 5x2 = 20 weeks). Patients were randomised to receive concomitant medication for 48 weeks with azathioprine (A) 50 mg fixed dose for 24, 36 or 48 weeks (APC) or a placebo. Each active treatment arm was made up to 48 weeks with placebo for 28, 24, or 12 weeks, so all patients took 48 weeks of medication.

The medication was prepared by and stored at The Leprosy Mission Research Centre, Delhi. Numbered treatment packs were made up and delivered to the centres. Specially designed forms were used for each stage of the recruitment, consent, assessment, laboratory investigations and follow-up process.

Case definitions, inclusion and exclusion criteria: [6]

The following patient based definitions were used

Paucibacillary (PB) leprosy—when a patient had five or fewer well-demarcated, hypo-pigmented and anaesthetic skin lesions, and/or one peripheral nerve thickened.

Multi bacillary (MB) leprosy—when a patient had more than five skin lesions and/or more than one nerve involved.

Skin Type 1 Reaction—when patient had erythema and oedema of skin lesions.

Nerve Function Impairment (NFI)—present when a patient had new sensory impairment, motor impairment or both. Nerve pain alone was not included in the definition of neuritis.

New nerve function loss–is ‘New’ when it occurred within the previous six months. This was established by asking the patient about symptoms and duration of nerve function loss.

Old nerve function loss—is ‘Old’ when it started six months or more before the date of presentation. This was established by asking the patient about symptoms and duration of nerve function loss.

Motor function loss—is present when there was a muscle score below five in any of the muscles on voluntary muscle testing. The nerves tested were facial, ulnar, median, radial and lateral popliteal with the following muscles/movement strengths: orbicularis oculi, abductor digitii minimi, abductor pollicis brevis, wrist extension, tibialis anterior.

Sensory function loss—is defined as a loss of two or more sensory points on Semmes Weinstein testing in the area supplied by a sensory nerve. Sensory testing was done for ulnar, median and posterior tibial nerves.

Worsening of motor function–is defined as a change in one or more than one grade in the voluntary muscle testing.

Worsening of sensory function—is defined as a change in two or more than two points in the sensory testing.

Nerve recovery—is when the NFI scores regain normal values for either sensory or motor functions.

Nerve improvement—is when the NFI scores improve from the baseline value for either sensory or motor functions but does not regain normal values.

Most severely affected nerve—is a nerve with a score of 3 on motor testing and /or 1.5 on sensory testing.

Least affected nerve—is a nerve with a score of 1 on motor testing and/or 0.5 on sensory testing.

Recurrent reactional skin lesions—are defined as newly erythematous lesions that have either developed whilst on steroids or when patient has stopped steroids.

Restarting steroids–is restarting or increasing steroid therapy during the study in the presence of worsening nerve function or recurrent skin reactions as defined above.

Defaulter–is a patient who did not return to the hospital within four weeks of the last visit and so is removed from the study.

Withdrawn–is when a patient is removed from the study due to adverse effects.

Primary outcome

Improved combined score- measured by skin, motor and sensory scores.

Secondary outcomes

1. Prevention of recurrent skin reactions.
2. Prevention of recurrence of neuritis during or after treatment

Measurement of sensory function

Sensory testing (ST) was performed using Semmes-Weinstein monofilaments (SWM) (Sorri-Bauru, Bauru, São Paulo, Brazil) at designated test sites on the hands and feet.[11] The sensation in the areas of skin supplied by the ulnar and median nerves was tested with 2g SWM at six sites. Sensation on the feet was tested using 10g SWM at four sites. For both sets of sensory testing a score was developed. For each nerve the score ranged from 0–1.5 depending on the number of sites at which the monofilament was perceived. The range of scores for each foot was (0–1.5).The sensory scores were summated on every visit. (See Appendix 1).

A similar method of assessment was used in a published study. [6]A score of 0 for an individual nerve indicated that complete sensation was present and a score of 1.5 that there was no sensation in the area supplied by that nerve. A patient with a sensory score of 3 either had slight impairment at several points in different nerves or two nerves with complete loss of sensation. A modification of the Walker scale was needed because the two studies used different sets of monofilament for sensory testing. In the AZALEP study 2 and 10 gram monofilaments were used on the hands and feet respectively whereas in the Walker study 2 and 10 gram monofilaments were used on the hand, 10 and 300 gram monofilaments were used on the feet.

Measurement of motor function

Voluntary muscle testing (VMT) was assessed using the modified Medical Research Council (MRC) grading of power. The grading was modified in our scores: a MRC grade 5 = 0, 4 = 1, 3 = 2 and 2, 1 and 0 were grouped together as 3. The scores range from 0–3 for each muscle with a total range of 0–30. The scores for each muscle were summated on each visit. A score of 0 indicated completely intact muscle power and 30 would indicate severe weakness in all the muscles tested. A score of 9 could indicate loss of function in three muscles or slight weakness in all muscles (See supporting Information).

Combined score

The skin, sensory and motor scores were summated for each patient on each visit. Trial outcomes were assessed by looking at score differences.

For each individual nerve the presence of new nerve damage was determined from the patient’s history and VMT/ST. New nerve damage had to be present for the patient to be entered into the study. Old nerve damage was separately recorded because it was not expected that these nerves would improve.

Inclusion criteria

Patients with PB and MB leprosy were included if they had

• acute neuritis,
• reactional skin lesions,
• or both the above

Patients already on steroid therapy (started within the past four weeks) were included if they presented with new neuritis. Patients taking or having completed MDT were eligible.

Exclusion criteria

The following exclusion criteria (all defined in the protocol) were applied: age less than 15 years or more than 60 years, weight less than 30 kg, confirmed pregnancy, on treatment for tuberculosis, known HIV sero-positivity, hepatic dysfunction, bone marrow dysfunction, splenomegaly, hypertension and diabetes, Erythema Nodosum Leprosum (ENL) reactions. Patients unable to comply with monitoring and follow up requirements were also excluded.

All patients had a full blood count (haemoglobin, white cell, differential and platelet counts), renal function test (serum creatinine), liver function tests (SGOT & SGPT) and a random blood sugar done to detect underlying conditions for exclusion.

Ethical approval

Ethical approval for this study was obtained from both the London School of Hygiene & Tropical Medicine, London UK and the Ethics Committee of The Leprosy Mission Trust India on 8th February 2008.

This trial was registered with the Indian Council of Medical research clinical Trial register as a clinical trial Number—REFCTRI/2016/12/007558

Informed Consent was taken from patients who were eligible to be included in the study.

All eligible patients were invited to participate in the study by the study Medical Officer (MO). They received a detailed information sheet (Form 1.0) about the Azathioprine study (in the local language); a patient counsellor helped them understand the study details. The patients then had the above investigations. Those found eligible returned to the study MO, where they gave their signed informed consent (Form 2.0) to participate in the study, and were included.

Patients who were either ineligible for trial entry or who did not wish to participate were treated as per the routine practice in that hospital. Patients were also informed that if they did not consent, this would not affect their usual treatment.

Sample size calculation

The sample size calculation was based on the expected improvements in the combined scores (skin, sensory & motor) that the addition of azathioprine to prednisolone would produce. It was calculated that the addition of azathioprine would produce a 25% improvement in the combined scores. This would be a score of 4 allowing for an alpha of 0.05 and beta of 0.80, the minimum sample size is calculated as follows:

We assumed a ‘lost to follow up’ rate of 15%, and dropout rate due to adverse reactions of 10%, so minimum of 78 patients would be required per arm, and a total of 312.

Randomisation & allocation to treatment arms

The staff at the centres were blinded to the randomisation. The Head of the Research Resource Centre (RRC), using Random Sampling Numbers prepared the confidential allocation into four arms, which was balanced for each centre, and created lists with an unique serial number. The allocation for each patient was kept confidential at the RRC.

The packing was done at RRC in small daily pill boxes with the appropriate amounts of each drug for each arm for four weeks. The boxes were prepared for 48 weeks for each patient. Thus there were 12 boxes for each patient, distributed to the respective centres by courier.

Drug preparation

The drugs were stored in cool dry rooms both at RRC and at the centres. Drugs were ordered in batches to ensure that they were within the active period after manufacture.

The placebo tablet was identical to the Azathioprine tablet.

Azathioprine Tablets BP 50 Mg (TRANSIMUNE*) and the placebo tablets were manufactured by Troikaa Pharmaceuticals Ltd. Thol-382 728, Gujarat, India.

Prednisolone Tablets I.P were manufactured by Comprehensive Medical Services India, (Essential Drugs Project) Riverside, P.B.No.988, Manapakkam, Chennai -600 089.

Recruitment

Physiotherapists in each hospital identified new eligible patients. The patient had clinical and laboratory investigations according to the flow chart (Appendix 2) and the clinical history with details of skin type 1 reaction, nerve function impairments and other clinical details was recorded. The pre-treatment assessment form was filled in; they were given a box with four weeks treatment and a date for the follow up visit.

Follow up and monitoring

Patients were followed up fortnightly for the first eight weeks and then at four week intervals, with full clinical and neurological assessments and laboratory investigations done at each visit.

If the scores had worsened, the patients were observed for seven days, with repeat testing and the protocol for increasing prednisolone was followed. Compliance with the medication was recorded. Possible adverse effects were detected by relevant questioning and investigations.

Any participant who did not return for a follow up for more than two weeks was contacted at his / her home by phone or personal visit and invited to return. Any patient who returned to the hospital within four weeks of the last visit continued in the study and those who did not return were classed as defaulters.

In patients who developed infections during the first 20 weeks, their dose of prednisolone was tapered more quickly (decreasing by 5mg every three days) and stopped, and antibiotic therapy relevant to the presumed infection given. In patients who were on MDT and developed anemia, dapsone was stopped. If the adverse events resolved within four weeks, the patient was restarted on the drugs and continued in the study. If this period exceeded four weeks or the adverse event was severe the patient was withdrawn from the study.

Criteria for restarting or increasing prednisolone

If the neuritis worsened or there was a recurrence of type 1 skin reaction during the first 20 weeks, the dose of prednisolone was increased to the preceding dose resulting in a longer duration of steroid therapy. If worsening occurred after 20 weeks, when prednisolone treatment had finished, the patient was given a 12 week course of prednisolone, starting with 40mg as in the protocol (two weeks each of 40, 30,20,15,10 & 5 mg of prednisolone).

Monitoring and management of adverse effects

Potential adverse effects of steroids, azathioprine and MDT were closely monitored. Protocols were developed for the investigation and management of all complications.

Adverse effects and deaths were discussed by the clinical team and ascribed when possible to one of the drugs. Deaths were investigated and the cause of death established by the MO. The contribution of Azathioprine and prednisolone to the cause of death were reviewed.

Documentation

All the patients’ details were recorded in predesigned forms designed for the study, at baseline and at each subsequent visit. These covered Screening for Eligibility, Registration for Trial, Informed Consent, Baseline History & Examination, Baseline Nerve Function Measurement, Baseline Lab Investigations.

Data management

Data from the clinical trial including the baseline data were computerised using dedicated software as well as on MS Excel sheets. Data was transferred into Statistical Package for Social Sciences and analysed.

The trial data is stored at the Leprosy Research Centre, Delhi. It can be obtained from the Head of the Leprosy Mission Research Centre, India, currently Dr annamma John.

Statistical analysis

Chi-square testing was used to compare the variables such as age, sex, type of leprosy.

For each of the primary and secondary outcomes, the differences between the baseline and end of study were computed, for each arm and the paired t-test was used to determine the statistical significance. The actual p-value was noted and inferences made accordingly using the conventional 5% and 1% levels.

The differences between the patients receiving placebo and each of the three Azathioprine treatment arms were also tested for statistical significance using the independent t-test for the various outcomes.

A modified intention to treat analysis was done on the outcomes for all the patients entered in the study (345) excluding those who had an extra course of prednisolone. A per protocol analysis was done on the patients who took the complete course of treatment and did not receive additional prednisolone (134). Outcomes for skin, motor and sensory testing were compared for patients in the four treatment arms. Median improvement scores were calculated and the differences tested for statistical significance using the Kruskal-Wallis test. Survival curves using Kaplan-Meier method for recurrence events were calculated for each arm.

Baseline analysis

Three hundred and forty-five patients (86.1% males and 13.9% female), age range 15 to 60 years, were recruited from the four centres.

Three hundred and thirty-six (97.4%) of the patients had Multi Bacillary leprosy and Ridley-Jopling types Borderline Tuberculoid (BT)62.3%, Borderline Borderline (BB) 5.5%, Borderline Lepromatous (BL) 21.7%, and polar Lepromatous (LL) 5.8%. 80% of the patients were starting MDT (40%) or on MDT (40%) and 20% had completed MDT.

Table 1 shows that 345 patients recruited had similar distributions of skin reaction and/or the presence of sensory and motor impairments and skin reaction in each centre and for each trial arm. Skin reaction alone (36.8%) was the commonest reason for recruitment, followed by new sensory and/or motor damage alone. Thirty-six(4%) had new nerve function impairment.

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Table 1. Clinical Features, Sensory, Motor impairment and Skin Reaction by arm for 345 patients.

https://doi.org/10.1371/journal.pntd.0005348.t001

Outcomes

Two hundred patients completed the study. Fig 1 Azathioprine study Flow chart shows the outcome (completed, withdrawn, defaulted and died) for patients in each treatment arm. Default (20–26%) and withdrawal rates (5.7% to 25.5%) were lowest (20%) in the prednisolone only arm.

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Fig 1. Azathioprine study Flow chart.

https://doi.org/10.1371/journal.pntd.0005348.g001

Adverse events

Table 2 shows that Cushingoid features (43%) and infections (35%) were the commonest events occurring at comparable rates across the four arms. Gastrointestinal symptoms and anaemia were more common, but not significantly, in patients treated with azathioprine, and four patients on azathioprine developed psychosis. Fifty-two out of 345 patients were withdrawn due to adverse events, pregnancy and developing ENL. The withdrawal rates between the arms ranged from 9–24%. In patients developing adverse events study drugs were withheld and the patients were monitored more closely and managed according to the protocol.

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Table 2. Adverse Reactions encountered in the study (n = 345).

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Anaemia was the most common reason for withdrawal (Table 3), affecting 59.3% patients and a significant interaction was found between patients being on azathioprine and developing anaemia (proportion z-test, p < 0.05). Patients taking dapsone were also at higher risk of developing anaemia, presumably due to an interaction between these two drugs. Nausea, vomiting, gastritis, loss of weight and a general ill-health were common and nine patients were withdrawn. Four patients developed infections including multi-dermatomal herpes zoster (2), infective gastroenteritis and hepatitis. The cause of the gastroenteritis and jaundice was not identified.

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Table 3. Adverse conditions resulting in withdrawal (n = 59).

https://doi.org/10.1371/journal.pntd.0005348.t003

Four patients became pregnant during the study and the study drugs were stopped as soon as the pregnancy was diagnosed. The pregnancies were diagnosed at six weeks. Three women chose to have their pregnancies terminated and one delivered a healthy baby.

Three patients developed ENL during the study. The study drugs were stopped and the patients were managed separately for their new immune complication in the clinic. Two patients had hepatic and renal function abnormalities which resolved after per protocol management. One patient developed sub-acute intestinal obstruction associated with an undescended testis and had surgery and was withdrawn from the study.

Most patients were withdrawn during the 2nd (22%) and 3rd (20%) months and were taking azathioprine. Patients continued to be withdrawn over the next seven study months with no withdrawals in the 11th and 12th month.

Four patients died during the study and their details are summarized in Table 4. All four patients were taking azathioprine as well as steroids and MDT. For each patient who died we tried to establish the cause of death and to establish whether azathioprine, prednisolone was the likely cause of death.

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Table 4. Clinical Features and Laboratory investigations of patients who died.

https://doi.org/10.1371/journal.pntd.0005348.t004

Patient 1 PA1: This patient developed a high fever with loose stools. The differential diagnoses included viral fever and typhoid fever. He had been in the trial for 15 days. It is unlikely that the trial drugs caused his death.

Patient 2 PA92: This patient had a cardio-vascular accident (CVA) (diagnosis on death certificate). He developed steroid induced diabetes and had dyslipidemia. He had been in the trial for 24 weeks. His steroid treatment had been stopped at 20 weeks, four weeks before his death. We attribute his death to his underlying co-morbidity exacerbated by the steroid treatment.

Patient 3 SA 102: The cause of death in this lady was not established. She developed a pancytopenia after being on trial drugs for 12 weeks. Her azathioprine and MDT were stopped. She also developed progressive anaemia, high fever, and cough and there was a possibility that she had TB. An unvalidated PCR test for M. tuberculosis DNA was positive and she had hilar lymphadenopathy on chest X-ray. She was not tested for HIV. She died in another hospital in Delhi of unidentified infection. Her death was probably related to her taking azathioprine.

Patient 4 CA 01: This man had a probable myocardial infarction (MI) and sepsis. He was on the study drugs for 22 days. He had pre-diabetes and developed sepsis after starting medication. This could have been due to the steroid treatment or the azathioprine. The death also occurred soon after starting trials drugs so it is unlikely to be due to azathioprine.

Intention to treat analysis

The trial outcomes were assessed by comparing the baseline with end of study clinical scores for each patient in each treatment arm. An Intention to Treat Analysis was done for 279 of the 345 patients entered into the study (excluding 66 patients who received a second course of prednisolone). For patients who did not complete the study (n = 145) their last assessment was taken as their endpoint). The combined score change and then the individual score components (skin, sensory, motor) are presented here.

Fig 2 shows the effect of treatmentin the 4 treatment arms for the 4 parameters, combined score, skin, sensory and motor scores differences for 279 patients. Three patients were worse and 65 patients had no or little change (0, 0.5, and 1). The median change in patients in arms 1, 2 and 3 was 3.0, and 4.0 for patients in arm 4. Sixteen (5.7%) patients improved substantially with score differences 10 and more. The baseline and endpoint score differences for patients in each arm were highly significant (p<0.001). However treatment with azathioprine did not improve outcomes, when the azathioprine treatment groups were compared with the steroids only treatment group, singly or combined. This is indicates that the improvement was due to the steroids and azathioprine did not enhance this improvement.

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Fig 2. Comparison of the score (Skin, Sensory & Motor) differences for patients in each treatment arm from Baseline to Endpoint (n = 279) and for each parameter combined, skin, sensory, motor and combined scores.

https://doi.org/10.1371/journal.pntd.0005348.g002

Fig 2 shows the skin score changes in 180 of the 279 patients who had Type 1 reaction (99 patients with only NFI were excluded). No patients deteriorated and 38 patients had no or little change (0 and 1). The median score changes for patients in arms 1, 2 and 4 were 3.0, and arm 3 was 4.0. Fifty-seven (31.6%) patients improved substantially, with score differences of 5 and more. The baseline and endpoint score differences for patients in arm 1, 2, 3 and 4 were highly significant (p<0.001), indicating that prednisolone treatment in these arms produced improvement and adding azathioprine did not improve skin outcomes in any arm.

Fig 2 shows the score differences for patients who had sensory loss (n = 104). No patients deteriorated and 69 (66.3%) patients had no or little change (0, 0.5 and 1). The median score change for patients in arm 1 and 2 was 0.5, and in arm 3 and 4 was 1.0. Seven (6.7%) patients improved substantially with a score difference of 5 and more. The score differences were significant for patients receiving 48 weeks azathioprine (p = 0.0002) and almost significant for patients in arms 1 and 3 (P values 0.0505 and 0.0512 respectively). This suggests that azathioprine might have a beneficial effect on sensory function.

Fig 2 shows the difference in motor scores for 152 patients who had motor loss. Three patients deteriorated and 72 patients had no or little change (0 and 1). The median change for patients in arms 1 and 2 was 2.0 and arms 3 and 4 was 1.0. Twenty (13.1%) patients improved substantially with score differences of 5 and more. Patients treated with prednisolone only and prednisolone plus 24 weeks of azathioprine had significant improvements in their score differences p 0.0002 and p 0.0001), no benefit was seen for treatment with 36 or 48 weeks of azathioprine with respect to motor function.

These figures also show that a few patients in the treatment groups responded to treatment, however their numbers were not significant.

Analysis for patients who completed 20 weeks of treatment

A similar analysis was done on patients (n = 253) who completed 20 weeks of treatment and we found similar significant improvements in the combined and skin, sensory and motor scores but azathioprine did not enhance improvement.

Recurrences

Recurrence was calculated in the 200 patients who completed the study and 72 (36%) had recurrences. There were 21 (32.8%), 23 (53.5%), 16 (34.8%) and 12 (25.5%) recurrences in each arm respectively. The first recurrence occurred at 16 weeks and continued throughout the study. Sixty-six patients were given a further course of prednisolone (18, (28.0%), 21 (48.8%), 15 (32.6%) and 12 (25.5%), and no statistical differences were found between the need for extra prednisolone between patients in the different treatment arms. Fig 3 shows the time to recurrence in each treatment arm and no significant differences were found between the four arms, showing that treatment with azathioprine did not delay the time to recurrence, although patients with the 48-week azathioprine treatment had the lowest rate of recurrence.

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Fig 3. Kaplan Meier Curve showing Time to recurrence in each treatment arm.

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Per protocol analysis

We also did a per protocol analysis for patients who completed the treatment course (n = 134). The findings were very similar to the Intention to Treat Analysis (ITTA). The combined and sensory scores are very similar in this group at 20 weeks and 48 weeks. However there was a late improvement in motor score.

Summaries of the analyses

The ITTA (n = 279) showed that there were significant baseline-end differences in scores for all the groups. Of the component scores, skin improved from baseline to end in all patients, sensory scores were only significantly improved in arm 4 and motor scores in arms 1 and 2. None of these differences were significantly different between the steroid and the steroid + azathioprine treatment arms. So prednisolone produces the benefit and azathioprine does not add to it. The small changes in treatments arms suggest that addition of azathioprine has a small effect in these patients.

Fig 4 shows the score differences for patients in each treatment arm and for the different parameters measured. The per protocol analysis show a similar picture with significant combined, skin and motor score changes from baseline to end for all treatment arms (Fig 4). Prednisolone treatment does not produce significant changes in sensory scores. This means that in this analysis for combined, skin and motor scores, prednisolone has an effect that azathioprine does not augment. For the sensory scores prednisolone is not effective. This also concurs with our finding that 67% of patients in the trial did not improve their sensory scores.

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Fig 4. Comparison of the score (Skin, Sensory & Motor) differences for patients in each treatment arm between Baseline and 48 weeks in study (n = 134) and for each parameter combined, skin, sensory and motor.

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The 20 weeks analysis shows a significant benefit for the combined score and a significant benefit for azathioprine treatment. The skin scores in this group all improved, the sensory scores for arms 1, 2 and 4 and the motor improvement were all significant. The differences between azathioprine and prednisolone only treated patients were only significant for the 24 week azathioprine in the motor score.

These findings can be summarised as showing that prednisolone contributes the most to improvement and there is some evidence that azathioprine gives some improvement to the motor function but azathioprine does not improve sensory function.

Nerve trunk function outcomes

Table 5 shows the nerve function outcomes at endpoint for all the peripheral nerve trunks by sensory and motor function. We compared the outcomes for each peripheral nerve trunk for patients receiving either prednisolone alone or APC. Each nerve was categorized into ‘unchanged’, ‘improved’ or ‘recovered’ separately for motor and sensory score differences at the end of the study No significant differences were found with the azathioprine treatment. The ulnar, posterior tibial and median nerves improved had the most improved sensory function and the median, lateral popliteal and ulnar nerves had the most improved motor function.

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Table 5. New NFI- All affected nerve compared from baseline to endpoint of study assessing both motor and sensory function (n = 134).

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Least and worst affected nerves

We hypothesized that the least affected nerve might show higher rates of recovery and the worst affected nerves the least improvement. These nerves were categorized by worst affected and least affected (definitions in Materials and Methods). Fifty-seven nerves were identified in the least affected category with recovery rates of 83% of nerves in the azathioprine + prednisolone treated groups and 78% in the prednisolone treated patients. Recovery occurred in all nerves with no nerve dominating. However there were only a few nerves in each category. In the worst affected nerve group a significant benefit for azathioprine treatment was found, with 82% worst nerves treated with Azathioprine plus steroids recovered and improved whereas only 66% worst affected nerves treated with steroids recovering (Z test p 0.0171).

Old nerve function Loss

We also tested the hypothesis that old nerve damage would show less improvement, by looking at the score differences for nerves that had been classified as having old damage. The sensory scores of three patients deteriorated and 72 patients had no or little change (0, 0.5 and 1). The median change for patients in all four arms was 0.0. One out of 82 patients improved substantially with score difference 5 and more. Motor scores of five patients deteriorated and 39 patients had no or little change (0 and 1). Two patients improved by 5 and more. The median change for patients in arm 1, 3 and 4 was 0.0, and arm 2 was 1.5. Treatment with azathioprine did not affect old damage for either motor or sensory scores (comparison made between arm 1 and 2, 1 and 3, 1 and 4). This shows that most patients with old motor and/or sensory nerve damage do not improve.

We analysed the score changes for all patients in the ITTA and found the following levels of change percentage wise for the combined treatment groups with the following categories, worse, static, improved and improved substantially. Combined (1.07, 23.2, 69.8, 5.7) Skin (0.0, 21.1, 47.3, 31.6) Sensory (0, 66.3, 27.0, 6.7) Motor (1.97, 47.3, 37.6, 13.1) Fig 5 shows the score changes for the whole cohort of the Intention to treat analysis by type of change and for each parameter combined, skin sensory and motor)

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Fig 5. Score Changes by type of change and for each parameter (combined, skin, sensory and motor) for the whole cohort by the Intention to treat analysis (ITTA) (n = 279).

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