A master protocol to investigate a novel therapy acetyl-L-leucine for three ultra-rare neurodegenerative diseases: Niemann-Pick type C, the GM2 gangliosidoses, and ataxia telangiectasia.

BACKGROUND: The lack of approved treatments for the majority of rare diseases is reflective of the unique challenges of orphan drug development. Novel methodologies, including new functionally relevant endpoints, are needed to render the development process more feasible and appropriate for these rare populations and thereby expedite the approval of promising treatments to address patients' high unmet medical need. Here, we describe the development of an innovative master protocol and primary outcome assessment to investigate the modified amino acid N-acetyl-L-leucine (Sponsor Code: IB1001) in three separate, multinational, phase II trials for three ultra-rare, autosomal-recessive, neurodegenerative disorders: Niemann-Pick disease type C (NPC), GM2 gangliosidoses (Tay-Sachs and Sandhoff disease; "GM2"), and ataxia telangiectasia (A-T). METHODS/DESIGN: The innovative IB1001 master protocol and novel CI-CS primary endpoints were developed through a close collaboration between the Industry Sponsor, Key Opinion Leaders, representatives of the Patient Communities, and National Regulatory Authorities. As a result, the open-label, rater-blinded study design is considerate of the practical limitations of recruitment and retention of subjects in these ultra-orphan populations. The novel primary endpoint, the Clinical Impression of Change in Severity© (CI-CS), accommodates the heterogenous clinical presentation of NPC, GM2, and A-T: at screening, the principal investigator appoints for each patient a primary anchor test (either the 8-m walk test (8MWT) or 9-hole peg test of the dominant hand (9HPT-D)) based on his/her unique clinical symptoms. The anchor tests are videoed in a standardized manner at each visit to capture all aspects related to the patient's functional performance. The CI-CS assessment is ultimately performed by independent, blinded raters who compare videos of the primary anchor test from three periods: baseline, the end of treatment, and the end of a post-treatment washout. Blinded to the time point of each video, the raters make an objective comparison scored on a 7-point Likert scale of the change in the severity of the patient's neurological signs and symptoms from video A to video B. To investigate both the symptomatic and disease-modifying effects of treatment, N-acetyl-L-leucine is assessed during two treatment sequences: a 6-week parent study and 1-year extension phase. DISCUSSION: The novel CI-CS assessment, developed through a collaboration of all stakeholders, is advantageous in that it better ensures the primary endpoint is functionally relevant for each patient, is able to capture small but meaningful clinical changes critical to the patients' quality of life (fine-motor skills; gait), and blinds the primary outcome assessment. The results of these three trials will inform whether N-acetyl-L-leucine is an effective treatment for NPC, GM2, and A-T and can also serve as a new therapeutic paradigm for the development of future treatments for other orphan diseases. TRIAL REGISTRATION: The three trials (IB1001-201 for Niemann-Pick disease type C (NPC), IB1001-202 for GM2 gangliosidoses (Tay-Sachs and Sandhoff), IB1001-203 for ataxia telangiectasia (A-T)) have been registered at www.clinicaltrials.gov (NCT03759639; NCT03759665; NCT03759678), www.clinicaltrialsregister.eu (EudraCT: 2018-004331-71; 2018-004406-25; 2018-004407-39), and https://www.germanctr.de (DR KS-ID: DRKS00016567; DRKS00017539; DRKS00020511).

Changes in liver tests during 1-year treatment of patients with Type 2 diabetes with pioglitazone, metformin or gliclazide.

AIMS: Patients with Type 2 diabetes are at increased risk of liver damage. Therefore, it is of particular importance to investigate the hepatic effects of drugs used to treat such patients. METHODS: Liver testing results performed in four 1-year, randomized, double-blind studies comparing effects of pioglitazone, metformin or a sulphonylurea, gliclazide, in the treatment of over 3700 patients with Type 2 diabetes have been analysed. RESULTS: Pioglitazone caused reductions in mean levels of hepatic enzymes of between 3 and 18%, whilst gliclazide caused small increases of between 3 and 13%. Metformin treatment showed either small mean increases or decreases. More patients receiving pioglitazone had liver tests within the normal range at the end of treatment (> or = 87%) compared with patients receiving metformin (> or= 80%) or gliclazide (> or = 75%). Slightly fewer patients with pioglitazone than with comparators showed a large increase (> 3 upper limit of normal) in alanine aminotransferase levels at any time during treatment (pioglitazone 0.9%, metformin 1.9%, gliclazide 1.9%). CONCLUSIONS: During pioglitazone treatment there is a reduction in liver enzyme levels. Although the mechanism of this effect is not clear, the results demonstrate potential beneficial effects on the liver during treatment of patients with Type 2 diabetes with pioglitazone.

Cardiovascular effects of treatment of type 2 diabetes with pioglitazone, metformin and gliclazide.

Cardiovascular mortality and morbidity are increased in patients with type 2 diabetes. However, there are few data from clinical trials comparing cardiovascular effects of alternative oral anti-diabetic agents. Major cardiovascular outcomes during four one-year, double-blind trials in over 3700 patients with type 2 diabetes randomised to either a thiazolidinedione, pioglitazone, metformin or a sulphonylurea, gliclazide treatment have been combined. Mean blood pressure was slightly reduced by all treatments, with pioglitazone treatment resulting in the largest falls (approximately 1.5 mmHg). Hospitalisations for cardiac or cerebrovascular events were similar with the different treatments. Overall mortality was seven of 1857 for pioglitazone and 10 of 1856 for non-pioglitazone treatments, of which three and six were cardiac deaths, respectively. The incidence of congestive cardiac failure was similar with pioglitazone (12/1857) and non-pioglitazone (10/1856) treatments. The results show similar cardiovascular outcome for the three different treatments over a one-year period, but demonstrate interesting differences, which will require longer-term formal outcome studies to determine their significance.

Reintervention as a clinical trial endpoint after peripheral arterial bypass surgery.

BACKGROUND: Graft patency is usually the primary endpoint in studies of peripheral arterial bypass surgery, but gives only a limited indication of clinical outcome. The aim of this study was to evaluate reintervention as a study endpoint after femorodistal bypass surgery. METHODS: The database from a multicentre, prospectively planned study of 517 patients undergoing femorodistal bypass for severe ischaemia was used to investigate the predictive value of technical endpoints. Clinical symptoms, graft patency, vascular interventions and clinical outcomes were recorded for 12 months after operation. RESULTS: Complete follow-up data were obtained on 498 patients (96 per cent). Success in terms of patients' need for reintervention agreed with clinical outcome in 90 (95 per cent confidence interval (c.i.) 87-93) per cent of cases. Primary and secondary patency agreed with the clinical outcome in 80 (95 per cent c.i. 77-84) and 81 (95 per cent c.i. 78-85) per cent of patients respectively. However, the best agreement with clinical outcome was obtained from the composite endpoint of 'patient alive without reintervention': 92 (95 per cent c.i. 90-94) per cent. CONCLUSION: Recording the number of patients who did not need reintervention for 12 months after femorodistal bypass gave a more accurate assessment of the number with clinical improvement than was obtained by recording bypass graft patency. Inclusion of patient survival in a composite endpoint increased the clinical relevance of this endpoint in patients with severe ischaemia who had femorodistal bypass surgery.

Safety profile of pioglitazone.

The safety profile of pioglitazone has been evaluated in trials including over 5,400 subjects, of whom over 3,500 received active treatment resulting in over 2,500 patient-years of exposure. Since its launch, over 1.4 million patients have been prescribed pioglitazone. This paper will examine the clinical trial tolerability and safety data available for pioglitazone. Safety was evaluated both as monotherapy and in combination with other antihyperglycaemic drugs. All studies had a placebo-controlled, double-blind, randomised, parallel-group, multi-centre design, in which pioglitazone was administered once daily over a period of 16-24 weeks. Most trials also had a long-term open label extension. In these trials, adverse events were recorded, as were details of laboratory blood values, urine analysis, vital signs and electrocardiograms. In addition, specific studies were conducted to examine any effects of pioglitazone on cardiac structure and function, and body composition. This paper will also briefly review data available from post-marketing surveillance.

Graft material and results of platelet inhibitor trials in peripheral arterial reconstructions: reappraisal of results from a meta-analysis.

AIMS: To investigate the characteristics of published trials in order to establish the origin of the differing results obtained in trials of platelet inhibitors after peripheral bypass procedures. METHODS: Analysis of the information from 11 randomised, controlled trials of platelet inhibitors after peripheral bypass procedures published up until 1999 and involving 2302 patients undergoing peripheral bypass operations, 1250 of whom were treated with platelet inhibitors. RESULTS: There is a significant treatment benefit of platelet inhibitors on meta-analysis of the trials, but a significant heterogeneity amongst the individual trial results. The proportion of patients in a trial with prosthetic grafts was a significant factor in explaining the heterogeneity. Proportion of prosthetic grafts was associated with sample size and with the proportion of grafts above the knee, but these were not found to make an independent contribution to the heterogeneity observed. The platelet inhibitor regimen used, the severity of ischaemic symptoms and the proportion of smokers included were also not found to be important. CONCLUSIONS: The improvement of graft patency by aspirin and related platelet inhibitors in clinical trials in peripheral bypass procedures can be attributed to an effect on patients with prosthetic grafts. There is little evidence that these agents prevent occlusion of vein grafts. The conclusion of an earlier meta-analysis that antiplatelet agents should be used for all bypasses is not supported.

The safety and tolerability of candesartan cilexetil in CHF.

The management of congestive heart failure (CHF) continues to represent a major therapeutic challenge. The primary goal of any treatment is the improvement of symptoms with a reduction in CHF related morbidity and a neutral or beneficial effect on mortality. The number of hospitalisations is considered an important measure of morbidity and quality-of-life in these patients. This pooled safety analysis was performed on adverse event data from five placebo-controlled studies involving a total of 1893 patients, 1287 of whom received candesartan cilexetil and 606 of whom received placebo. These were the only placebo-controlled phase II and III studies of candesartan safety available at the time of the analysis, and investigated the efficacy and safety of candesartan cilexetil in patients with CHF. None was designed as an endpoint trial. A blinded, independent review of all adverse event data was performed to assess all-cause mortality and unexpected deaths, and hospitalisations for acute deterioration of CHF, chronic progression of CHF, other intercurrent events, or accidental injury/attempted suicide. The descriptive analysis included crude and cumulative incidence rates for mortality and cardiac and non-cardiac morbidity using the Kaplan-Meier method and the log-rank test. The sample population was predominantly (approximately two thirds) male, with a median age of 61 years (range: 20-89 years). The median age for women in the sample population was 66 years (range: 26-86 years). Patients received candesartan cilexetil, 2-32 mg, over a median period of 84 days (range: 1-418 days), or placebo over a median period of 85 days (range: 1-398 days). The results demonstrated a clinically non-significant trend for all relevant events (deaths and hospitalisations, whether related to CHF or not) to occur less frequently in patients receiving candesartan cilexetil than in patients receiving placebo (deaths - candesartan cilexetil: 1.6%, placebo: 1.8%; hospitalisations - candesartan cilexetil: 7.2%, placebo: 10.9%). There was a significant treatment difference in CHF hospitalisations (candesartan cilexetil: 3.0% vs. placebo: 5.6%). The time to event analysis revealed that significantly fewer hospitalisations due to CHF occurred in the group receiving candesartan cilexetil than in the group receiving placebo. This treatment difference persisted throughout therapy (log-rank test; p < 0.028). These results show the safety of candesartan cilexetil, compared with placebo, in the treatment of patients with CHF.

Adjuvant medical therapy in peripheral bypass surgery.

BACKGROUND: A review was conducted of published clinical trials of adjuvant medical therapy in infrainguinal bypass procedures to evaluate the strength of the evidence for the use of various agents. METHODS: Trials were identified by literature search. The methods used were reviewed and the results with each agent tested were assessed taking into account the soundness of the study design. RESULTS: Thirty-three studies were identified; fewer than half had a randomized and double-blind design. Most were single-centre studies including a mixture of different surgical procedures and patients with varying degrees of lower limb ischaemia. Clinical outcomes were seldom reported. The median sample size was 61. The median follow-up duration was 12 months, but was often not standardized for all patients in a trial. Only aspirin in prosthetic grafts and ticlopidine in vein grafts have been shown in well designed, double-blind, randomized, controlled trials to reduce the likelihood of occlusion in infrainguinal bypass grafts. CONCLUSION: The majority of the trials reviewed had significant deficiencies in their design, reducing the reliance that can be placed on their results. Further studies are required to investigate adequately the effectiveness of existing medical therapies for the maintenance of infrainguinal bypass grafts.

Seasonal variation of Raynaud's phenomenon secondary to systemic sclerosis.

OBJECTIVE: Patients with systemic sclerosis (SSc) were assessed for 12 months to quantify the seasonal variation in Raynaud's phenomenon (RP) in patients with an underlying connective tissue disease. METHODS: Eighteen patients with SSc (17 limited, 1 diffuse type) were studied. Raynaud's attacks were recorded in a daily diary for four 2-week periods at 3 month intervals. Daily number and duration of attacks and overall severity of RP were calculated for each 2-week period. Mean daily temperatures, measured and perceived, were obtained for each period. RESULTS: In winter, patients had a mean of 2.9 attacks/day (SD +/-1.1), daily duration 70 minutes (SD +/-48) and a severity of score of 4.1 (SD +/-2.0) out of 10. All 3 variables correlated with ambient outdoor temperature and varied significantly over the 12 months (p<0.001) with mean reductions of 48, 50, and 56% respectively from winter to summer. Only 3 of 18 patients reported no attacks during the summer period. The mean measured and perceived outdoor temperatures increased from winter to summer by 10.6 and 14.3 degrees C, respectively. CONCLUSION: For patients with SSc, RP is a problem throughout the year. Symptoms may be reduced by about 50% in the summer months, but few patients experience complete relief.

Quantitative assessment of walking activity after total hip or knee replacement.

Accumulating data suggest that the amount of use, and not simply the duration in situ, influences the wear and survival of total joint replacements. An electronic, digital pedometer was used to record the number of steps taken by 111 non-randomized volunteers who had had at least one total hip or knee replacement. The patients averaged 4988 steps per day, which extrapolates to approximately 0.9 million cycles per year for each joint of the lower extremity. Average activity ranged widely from 395 to 17,718 steps per day, an approximately forty-five-fold difference. The most active patient walked more than 3.5 times the average number of steps per day. Age was significantly associated with activity (p = 0.048), but there was a high degree of variability (standard deviation, 3040 steps per day). Patients who were less than sixty years old walked 30 per cent more on average than those who were sixty years old or more (p = 0.023). Men walked 28 per cent more on average than women (p = 0.037), and men who were less than sixty years old walked 40 per cent more on average than the rest of the patients (p = 0.011). These data indicate that individual differences in the activity of the patient can be a substantial source of variability in rates of polyethylene wear in vivo. The pedometer is an inexpensive investigational tool with many potential applications, including standardizing wear measurements of joint replacements on the basis of gait cycles rather than time. This quantitative approach may provide prognostic information regarding the survival of joint prostheses. Pedometer data may also be useful for quantitative assessment of walking ability in outcome studies.

Candesartan cilexetil: safety and tolerability in healthy volunteers and patients with hypertension.

The tolerability and safety of candesartan cilexetil has been evaluated in over 5000 subjects enrolled into double-blind or open-label clinical studies. In double-blind clinical trials in patients with primary hypertension, candesartan cilexetil 2-16 mg once-daily was associated with a low incidence of adverse events and drug-related withdrawals, similar to placebo. The drug showed no evidence of dose-dependent adverse events and it was equally well tolerated by men and women and by elderly (> or =65 years) and younger (<65 years) patients alike. Candesartan cilexetil had no effect on blood glucose control or serum lipid profile in patients with type II diabetes. It was very well tolerated also when given in combination with hydrochlorothiazide or amlodipine and during long-term open-label therapy (up to 1 year). Candesartan cilexetil therefore possesses an excellent tolerability profile that extends to a wide variety of patients including the elderly and it does not aggravate co-existing risk factors such as hyperlipidaemia or glucose intolerance. It therefore appears to offer a better tolerated alternative to other commonly used antihypertensive agents.

Functional outcome analysis of operatively treated malleolar fractures.

OBJECTIVES: Assessment of functional outcome after malleolar fractures. DESIGN: Retrospective call-back review of 40 patients who agreed to assessment 8-24 months after malleolar fractures. SETTING: Acute care hospital/Level 1 trauma center with university-based orthopaedic residency. PTS/PARTICIPANTS: 1) 10 skeletally mature patients who agreed to a telephone request to return for review 8-24 months after isolated malleolar fractures (36 44B2.2, 3 44A2.3, 1 44C2.2). All had healed without apparent complications. 2) Control group of 40 age matched healthy individuals without ankle problems. INTERVENTION: ORIF with standard AO/ASIF techniques. MAIN OUTCOME MEASUREMENTS: Ankle score of Olerud and Molander, UCLA Activity Score, Pedometer count of average number of steps per day. RESULTS: Patients had a mean Ankle Score of 72 (+/-19.3) vs. 100 (+/-0) for controls (p < .01). The UCLA Activity Score averaged 6.0 (+/-1.95) for the patients vs. a mean of 9.43 (+/-1.0) for controls (p < .01). Patients took an average of 4,838 steps per day (+/-3,252) vs an average of 7,607 steps per day (+/-2,859) by controls (p < .01). CONCLUSIONS: Significant impaired function persists for most patients 8-24 months after malleolar fractures.

Prospective study of 713 below-knee amputations for ischaemia and the effect of a prostacyclin analogue on healing. Hawaii Study Group.

In 51 hospitals in six European countries 713 patients requiring below-knee amputation for ischaemic disease were studied prospectively. The patients were allocated randomly to receive standard postoperative treatment or standard treatment plus intravenous infusion of the prostacyclin analogue iloprost for 6 h per day over 14-21 days. Healing of the amputation stump and the need for reamputation at a higher level were similar in the two groups. Overall at 3 months 59 per cent of stumps had healed, 19 per cent of patients had required reamputation at a higher level, 11 per cent had died and the remaining 11 per cent remained with unhealed stumps. Preoperative characteristics were analysed as possible risk factors or markers for primary healing, reamputation and death. Previous arterial reopening procedures (surgical or radiological) almost doubled the chances of primary stump healing (P < 0.05). The surgeon's assessment of the likelihood of healing was wrong in 21 per cent of cases in which the operating surgeon thought that healing would probably occur and in 52 per cent of those in which it was thought healing was improbable.

Placebo controlled study showing therapeutic benefit of iloprost in the treatment of Raynaud's phenomenon.

Iloprost is a chemically stable analog of prostaglandin I2 showing the same properties as the naturally occurring substance, but with advantages of ease of handling and administration to patients. A double blind within patient comparison of intravenous iloprost and placebo was undertaken in 13 patients with Raynaud's phenomenon severe enough to warrant short term hospitalization for intravenous dilator therapy; thermography was used as one form of assessment. Our results, while showing improvements in frequency of Raynaud's attacks after iloprost compared with placebo, show no significant effects on other variables.

Iloprost in cardiopulmonary bypass procedures.

The inhibition of platelet aggregation during cardiopulmonary bypass and effects on post-operative placebo-controlled study of 145 patients. Significant preservation of platelet numbers and function were shown without significant haemodynamic problems, but no effect on cerebral deficits could be found. The use of iloprost in patients with severe thrombocytopenia seems justified, but the clinical benefits from its use in routine cardiopulmonary bypass remain to be shown.

Effects of iloprost and factors affecting outcome in patients with severe inoperable lower limb ischaemia. U.K. Severe Limb Ischaemia Study Group.

The effects of i.v. iloprost given for 14-28 days on six month outcome in patients with severe inoperable lower limb ischaemia were investigated in a double-blind placebo controlled study. More iloprost patients (64%) survived with a viable limb than placebo patients (42%). Iloprost improved prognosis in all subgroups of patients, but patients with lower presenting ankle Doppler pressures had a worse outcome than patients with higher pressures.

Retrospective comparison of iloprost with other treatments for secondary Raynaud's phenomenon.

One hundred and twenty seven patients who had Raynaud's attacks secondary to connective tissue disease received intravenous infusions of iloprost in controlled clinical trials. Results of previous treatments for Raynaud's attacks had been recorded by clinicians in 84 of these cases, allowing a comparison to be made with the response to iloprost treatment. Iloprost was reported by the patients as beneficial in 49 (58%) of 84 cases, whereas only 36 (43%) of the 84 patients had previously found any other treatment to be useful. Twenty four of 48 (50%) patients who had not responded to any previous treatment found iloprost to be of benefit. Success or failure of treatment with iloprost was not accurately predicted by the result of treatment with any other drug, except prostacyclin. This survey suggests that iloprost is a useful treatment for patients with severe secondary Raynaud's phenomenon and can be effective in patients unresponsive to other treatments.

Successful treatment of Raynaud's syndrome with Iloprost, a chemically stable prostacyclin analogue.

Twelve female patients with severe secondary Raynaud's phenomenon were treated in a randomized order with both placebo and Iloprost infusions. Infusions were for 5 hours on 3 consecutive days and Iloprost was administered at variable dosage from 1.0 to 3.0 ng/kg/min. A 6-week follow-up period was used between the two sets of infusions. A significant number of patients reported Iloprost had improved Raynaud's symptomatology compared with placebo and this effect lasted for up to 6 weeks. The number of attacks of Raynaud's as recorded by patients in diary books was similarly reduced after Iloprost. Digital and nail-bed blood flows measured by laser-Doppler methods were increased for up to 6 weeks after Iloprost, but not after placebo infusions. Iloprost may be a useful therapeutic agent in the treatment of severe secondary Raynaud's syndrome.