Treatment of Early Neuropathy in Leprosy.

The TENLEP Trials proposal builds on the findings of the INFIR Cohort Study and the recommendations of the NLR-funded international Workshop on Neuropathology in Leprosy in the Netherlands in 2007. At this workshop, several key research questions were prioritised. These included:

1. How effective is steroid treatment of sub-clinical neuropathy detected at diagnosis in reducing the proportion of patients with sensory and/or motor NFI one year after the start of MDT?

2. What is the optimal steroid treatment regimen for patients with clinical sensory and/or motor NFI of recent onset (<6 months)?



The TENLEP Trials will use a randomised double-blind controlled trial design to answer the above questions in 2 integrated trials. We have the following hypotheses:

Trial 1: Steroid treatment (20 weeks) of sub-clinical neuropathy detected at diagnosis will significantly reduce the proportion of patients with sensory and/or motor nerve function impairment 18 months after the start of MDT.

Trial 2: Steroid treatment of 32 weeks duration is more effective than treatment of 20 weeks duration in restoring nerve function in patients with clinical sensory and/or motor NFI of recent onset (<6 months).



All patients newly registered at the participating centres will be asked to consent to take part in the study. After consent, they will be enrolled in one of the two trials described above, depending on their nerve function status. They will then be randomised into a treatment or placebo group for Trial 1 or into one of two treatment arms for Trial 2. Patients who are not already in Trial 1 and who develop new NFI during the first 3 months of MDT will also be eligible for Trial 2. Outcomes will be assessed at the end of steroid treatment, and at 12 and 18 months after the start of MDT using monofilament test (MFT) voluntary muscle test (VMT), nerve conduction (NC), warm detection thresholds (WDT) and SALSA scale measurements. All nerve function assessment (NFA) will be blinded with regard to treatment status. Occurrence of all new or additional NFI events and leprosy reactions will be recorded. Outcomes will be compared between treatment groups with regard to nerve function, activity limitation, incidence of nerve function impairment events, and reactions and need of prednisolone treatment during follow-up.



The countries in which the study will take place are India, Bangladesh, Nepal, and Indonesia.

The TENLEP Trials proposal builds on the findings of the INFIR Cohort Study and the recommendations of the NLR-funded international Workshop on Neuropathology in Leprosy in the Netherlands in 2007. At this workshop, several key research questions were prioritised. These included:

1. How effective is steroid treatment of sub-clinical neuropathy detected at diagnosis in reducing the proportion of patients with sensory and/or motor NFI one year after the start of MDT?

2. What is the optimal steroid treatment regimen for patients with clinical sensory and/or motor NFI of recent onset (<6 months)?



The TENLEP Trials will use a randomised double-blind controlled trial design to answer the above questions in 2 integrated trials. We formulated the following hypotheses:

1. Trial 1:

Steroid treatment (20 weeks) of sub-clinical neuropathy detected at diagnosis will significantly reduce the proportion of patients with clinical sensory and/or motor nerve function impairment 18 months after the start of MDT.

2. Trial 2:

Steroid treatment of 32 weeks duration is more effective than treatment of 20 weeks duration in restoring nerve function in patients with clinical sensory and/or motor NFI of recent onset (<6 months).

At intake, at the end of treatment, at 12 and at 18 months the following investigations will be done:

1. Nerve function assessment (NFA): Nerve Function Assessment will be done using the following methods:

A. History taking;

B. Motor nerve function:

i. Voluntary muscle testing (VMT) using the 0-5 modified MRC scale;

ii. Motor nerve conduction measurements (ulnar, peroneal, median);

C. Sensory nerve function:

i. Sensory testing using a standard set of 5 Semmes-Weinstein monofilaments (MFT);

ii. Warm detection testing WDT using the Thermal Sensory Analyzer II (ulnar, median, radial cutaneous, sural and posterior tibial);

iii. Sensory nerve conduction (SNC) measurements (ulnar, median, radial cutaneous, sural and posterior tibial).

2. Activities of daily living: A questionnaire-based ADL assessment will be done to evaluate possible consequences of neurological impairment at the activity level.

Trial 1:

Patients receiving prednisolone will start at a dose of 1 mg/kg/day, taken in the morning. To allow better comparison of treatment outcomes, two weight groups are discerned, one less than 50 kg (average of 45 kg) and the other more than 50 kg (average 60). These two weight classes will receive a differing total dosage, allowing similar dosage per kg. The dose will be tapered down quickly with 5 mg weekly till a plateau is reached of 0,3-0,5 mg/kg/day. Final tapering down will be done in the last 3 weeks. In the treatment arm a therapeutic dose of more than 0,3 mg/kg/day will be maintained for 17 weeks. The total course will be of 20 weeks duration.



NB: Patients receiving placebo will follow the same scheme, but now using placebo tablets that will be a replica of those containing prednisolone.



Trial 2:

Patients will start at a dose of 1 mg/kg/day, taken in the morning. To allow better comparison of treatment outcomes, two weight groups are being distinguished, one less than 50 kg (average of 45 kg) and the other more than 50 kg (average 60). These two weight classes will receive a differing total dosage, allowing similar dosage per kg. The dose will be tapered down quickly with 5 mg weekly till a plateau is reached of 0,3-0,5 mg/kg/day. Final tapering down takes place in the last 3 weeks.



In arm 1 a therapeutic dose of more than 0,3 mg/kg/day will be maintained for 17 weeks. The total course will be of 32 weeks, of which the first 20 weeks will be prednisolone and the remaining weeks will be placebo for the purpose of comparison with arm 2. To enable blinding of arm 1 and arm 2, patients in each arm will receive the same amount of tablets per day. In arm 1 this results in a combination of prednisolone tablets and placebo tablets (see figure).



In arm 2 a therapeutic dose of more than 0,3 mg/kg/day will be maintained for 29 weeks. The total course will be 32 weeks (see table 2).