Study TRX-015 was designed to assess the safety and efficacy of LMTX® at three doses in 891 patients diagnosed with mild to moderate Alzheimer’s disease. The main measures of efficacy (“primary outcomes”) used in the study were:
- The change in study subjects’ performance in two commonly used clinical assessments:
- The Alzheimer’s Disease Assessment Scale – Cognitive Subscale, known as ADAS-cog11
- The Modified Alzheimer’s Disease Cooperative Study – Activities of Daily Living, known as ADCS-ADL
- The safety and tolerability of LMTX® at doses of 150mg and 250mg per day given for up to 15 months were compared with a dose of 8mg per day
This 15-month study took place at 116 clinical sites in 16 countries. Of the 891 subjects randomized:
- 549 (61%) had moderate AD and 342 (39%) had mild AD;
- 755 (85%) were taking LMTX® as an add-on therapy and 136 (15%) were taking LMTX® as monotherapy;
- 357 (40%) were randomized to the control arm (8 mg/day, given as 4 mg twice daily), 268 (30%) were randomized to the lower dose arm (150 mg/day, given as 75 mg twice daily) and 266 were randomized to the higher dose arm (250 mg/day, given as 125 mg twice daily).
The modified intent-to-treat population (all patients taking the drug and having at least one post-baseline efficacy assessment) was 855 and the overall retention rate was 65%.
The top-line results (see Tables 2-4 in the Lancet publication, link below) can be summarised as follows:
- The study failed to achieve the primary efficacy endpoints for which it was designed; there was no difference between either of the two higher doses (150 mg and 250 mg/day) and the 8 mg/day control dose on the co-primary efficacy outcomes in the primary analysis model.
- The primary analysis model showed a highly significant effect of taking or not taking approved AD treatments whereby patients taking LMTX® as monotherapy declined significantly less than the those taking the control dose.
- A pre-specified variant of the primary analysis model confirmed that LMTX® as monotherapy produced statistically significant and clinically meaningful benefit on all primary and secondary clinical outcomes for the two higher doses compared with the control arm as randomised.
- In the monotherapy population, the reduction in rate of clinical decline was accompanied by MRI evidence of reduction in rate of progression of brain atrophy (see Supplementary Table 1 in the Lancet publication, link below).
- Differences in treatment effects between patients receiving LMTX® as monotherapy or add-on therapy could not be explained by any differences at baseline between these patient groups (see Supplementary Table 4 in the Lancet publication, link below).
- The overall safety profile of LMTX® was judged acceptable, with main adverse events related to the gastrointestinal tract and urinary system which is consistent with Phase 2 study results.
- The safety and tolerability profile was better at the 8 mg/day dose than at the higher doses.
An abstract from the trial was presented at the Alzheimer's Association International Conference (AAIC) in Toronto, Canada on 27th July 2016 and results were published in The Lancet in November 2016.