Ifakara Health Institute

Ifakara Health Institute
Bagamoyo Research and Training Center (BRTC)
PO Box 74
Bagamoyo, Coast Region
TANZANIA

Project Leader: Dr. Francis Mhimbara
Principal Investigator:
Dr. Lilian Tina Minja
Contact: Dr. Francis Mhimbara and Dr. Lilian Tina Minja
Phone: +255 754 291657 / +255 713 254563
Website: www.ihi.or.tz

16.5 Million Euro for PanACEA II

Rob Aarnoutse, Leon van Halder, and Martin Boeree signing the PanACEA II Grant Agreement

PanACEA II has been granted 16.5 million euro in their drug development programme to shorten and simplify treatment of tuberculosis. On February 24th 2017, the coordinating team from Radboudumc Nijmegen, Martin Boeree and Rob Aarnoutse, have signed the PanACEA Grant Agreement with Radboudumc’s chairman of the board of directors, Leon van Halder. On February 27th, the European and Developing Countries Clinical Trials Partnership (EDCTP) has countersigned the agreement which results in the project’s official start on March 1st 2017.

Building on PanACEA I, the objectives of PanACEA II are to complete the optimization of existing drugs and to evaluate two novel agents. Combination regimens will be tested that will shorten and simplify treatment for both drug-sensitive and drug-resistant tuberculosis. Trials will be conducted at 11 sites throughout sub-Saharan Africa, empowering African scientists in all aspects of an integrated and comprehensive programme for drug development. The capacity development programme, which stems from PanACEA I, will be expanded to strengthen African clinical trial sites and research capacity and to strengthen and transfer African scientific leadership.

The PanACEA II consortium will have their first official meeting on 7 and 8 March 2017 in Cape Town.

 

 

PanACEA in The Lancet Infectious Diseases

On October 26th, 2016 The Lancet Infectious Diseases published the most recent findings from the multi-arm, multi stage tuberculosis (MAMS-TB) trial of the PanACEA consortium. The MAMS-TB  trial investigated four new potential regimens for the treatment of tuberculosis.

Trial results show that the highest rifampicin dose tested (35 mg/kg) is safe and reduces the time to culture conversion in liquid media compared to the standard dose (10 mg/kg). The 35 mg/kg dose has promise to progress to phase 3 as an important component of future, shorter regimens to be assessed for improvement of relapse rates.

The data bring into question the utility of regimens with relatively low increases in the dose of rifampicin, suggesting that they are not likely to provide significant benefit or treatment shortening. In this light, the results suggest that higher doses than 35 mg/kg should also be evaluated for safety and efficacy.

Finally, this is the first time that a multi-arm adaptive trial design was successfully implemented in a multi-centre study in a high tuberculosis burden setting. This approach might accelerate tuberculosis regimen development at a reduced cost.

First Session PanACEA II in Liverpool

The preparations for PanACEA II have been in full swing with a meeting of a large part of the consortium in Liverpool. On October 26th 2016, the international group of partners met again to share thoughts and ideas about the continuation of PanACEA. Several presentations were held, results were shared and organisational issues were discussed.

 

PanACEA MAMS-TB-01 finds high-dose rifampicin may help shorten TB treatment

Press release – Nijmegen, Netherlands / Munich, Germany February 26th 2015:

At the annual Conference on Retroviruses and Opportunistic Infections (CROI), PanACEA, the Pan-African Consortium for the Evaluation of Antituberculosis Antibiotics, presented the results of its most recent phase IIb study (MAMS-TB-01). The most exciting finding from the study is that high-dose rifampicin results in faster killing of TB bacilli during treatment, compared to the current standard treatment.

The standard WHO-recommended TB treatment regimen (2 months of daily ethambutol, isoniazid, rifampicin and pyrazinamide followed by 4 months of daily isoniazid and rifampicin (2EHRZ/4HR)) involves taking the drugs daily for 6 months. This can make adherence to treatment hard, and has substantial costs to the health system and patients. Shortening the length of time treatment needs to be taken for, may help to reduce the burden on health systems, the costs of treatment, and make treatment easier for patients. PanACEA MAMS-TB-01 was set up to address this.

High-dose (35mg/kg) rifampicin, in combination with standard dose of isoniazid, pyrazinamide and ethambutol, showed a significant shortening of time to culture conversion with a covariate-adjusted hazard ratio of 1.75, 95% confidence interval (1.21-2.55) over the 12 weeks of experimental treatment. For comparison to previous TB trials, covariate-adjusted hazard ratios compared to control over 8 weeks were 1.99, 95% confidence interval (1.21-3.29). It was not possible to culture TB bacilli in sputum by 8 weeks in 56% of patients on the 35mg/kg arm compared to 42% of patients on the standard of care arm. These proportions were 80% and 70% respectively after 12 weeks.

Culture on solid media, which was a secondary endpoint, showed a similar although less marked result.

Chief Investigator Martin Boeree (Radboud University Nijmegen) says: “This is the largest reduction in time to culture conversion seen in any previous TB trial, to our knowledge. High doses of rifampicin may be an important component in shorter TB regimens in the future.”

The arm containing moxifloxacin with rifampicin 20mg/kg, pyrazinamide and ethambutol showed a borderline significance, hazard ratio 1.42 (95% confidence interval, 0.98-2.05) for improvement over control.

In an interim analysis conducted in early 2014, recruitment to both arms that included the new drug SQ109 were terminated, as it was clear that both regimens would not meet the predetermined hazard ratio of 1.8 using liquid culture and thus were unlikely to result in substantially improved regimen. Patients on these arms remained on treatment and in follow-up, and the now available data confirms the interim analysis decision.

Preliminary analysis of safety events showed no differences in side-effects in any of the arms as compared to control.

The MAMS-TB-01 trial enrolled 365 patients from 7 sites in Tanzania and South Africa in only 11 months. It used an innovative adaptive clinical trial design that allows several new regimens to be compared to the current standard, and incorporates interim analyses that allow for regimens that show little treatment shortening potential to be excluded from the trial at an early stage. 

Data on treatment up to week 26 and post-treatment follow-up will be analyzed and reported together with the results mentioned above in the main publication.

“We would like to thank our main donor, the EDCTP, for its support of this African-European consortium,” said Michael Hoelscher, sponsor representative. “We are pleased to have optimized one potential component of a future treatment-shortening regimen. This is, however, only the beginning of a series of phase I and II studies that will evaluate in a systematic manner at least 5 novel and improved TB drugs.“

Link to CROI Webcast: http://www.croiwebcasts.org/console/player/25685?mediaType=slideVideo&

Final PanACEA I Meeting in Alpbach, Austria

On January 25 – 28 the final PanACEA I meeting was held in Alpbach, Austria. PanACEA members of 11 countries (Belgium, Gabon, Germany, Great Britain, Kenya, Mozambique South Africa, Tanzania, The Netherlands, Uganda, and Zambia) attended the meeting. The newest results of the clinical studies, master and PhD studies and capacity development updates were presented.

panacea_meeting_alpbach

PanACEA in “World TB Day 2014 – Reach the 3 Million”

On March 24, 2014, Michael Hoelscher (LMU) presented “Advances in New TB Drug Development”, Tim McHugh (UCL) “Approaches to Monitoring Therapy” and Patrick Phillips (MRC CTU) “Drug Resistance vs. Drug Sensitive Trials “ at the “World TB Day – Reach the 3 Million” in London (www.who.int/campaigns/tb-day/2014/en). This conference, which was a joint venture between University College London (UCL) and the London School of Hygiene and Tropical Medicine (LSHTM), offered a platform to raise the awareness about the pandemic tuberculosis (TB) worldwide and presents the most current research of TB prevention and control efforts.
 
For a video of the presentations please see http://tb.lshtm.ac.uk/world-tb-day-2014-symposium-slides-and-video.

MAMS study has completed first interim analysis

PanACEA, the Pan-African Consortium for the Evaluation of Antituberculosis Antibiotics aims to develop TB regimens that significantly shorten treatment duration, funded by EDCTP. The consortium’s most recent phase IIb study (MAMS-TB-01) uses an innovative adaptive clinical trial design that allows the efficient evaluation of multiple regimens by incorporating interim analyses that allow for the early exclusion of regimens that show little treatment shortening potential.

Following the first scheduled interim analysis on March 3rd, the Trial Steering Committee (TSC) followed a recommendation of the independent data monitoring committee (IDMC) and has stopped the enrolment into two of the arms in the MAMS-TB trial: HRZQ and HR20ZQ. Patients that have already been enrolled into these arms will continue as laid out in the protocol.

The IDMC reviewed safety and efficacy data extensively including a number of sensitivity analyses and secondary efficacy endpoints. To-date the time at which patients have a negative culture is the best indication of future cure. Only treatment combinations that show a significant improvement in the speed at which they render patients culture negative are likely to shorten treatment. The predefined stopping rules of the MAMS trial were set to allow for early exclusion of regimens that were not likely to reach a hazard ratio of at least 1.8 at the end of the trial. This was based on the results from a study that evaluated a moxifloxacin substitution being studied in the ReMOXTB phase III trial that showed a hazard ratio of 1.68 (the OFLOTUB phase II trial). They recommended that recruitment to arm 2 (HRZQ) and 3 (HR20ZQ; see below) be terminated as there was insufficient evidence that these regimens could shorten treatment. Importantly, there was no evidence that either arm was inferior to standard treatment (the control arm) with regards to efficacy. There was, however, sufficient evidence that the other intervention arms HR35ZE and HR20ZM could shorten treatment to continue enrolling patients.

Since there were no indications of safety or inferiority concerns for SQ109, Sequella and partners will now undertake dose escalation and drug-drug interaction studies to see if a higher dose has potential to make a larger impact on sputum clearance. Analyses of intensive pharmacokinetics of SQ109 in combination with other drugs, especially rifampicin, will be used to determine the relationship between drug levels and bactericidal effects.

This result illustrates the strength of the MAMS approach, as normally the IDMC would not have recommended stopping these arms as there were no safety or inferiority concerns. The pre-specified stopping guidelines allowed the TSC the opportunity to stop these arms early, thereby saving resources and limiting the number of patients allocated to these regimens. This is an important consideration that reduces the number of patients enrolled in studies or arms that are unlikely to result in improved treatments and will speed the development of new TB medicines in the future.

The PanACEA consortium (http://panacea-tb.net/) is a partnership of 11 African and 7 European institutions and is led by three Chief Investigators at University of St. Andrews, Scotland (Prof. Stephen Gillespie), Radboud University Nijmegen / the Netherlands (Prof. Martin Boeree) and Ludwig Maximilians University, Munich / Germany (Prof. Michael Hoelscher). UCL is a major partner with the MRC-CTU at UCL and the Centre for Clinical Microbiology. The MAMS phase IIb trial started in May 2013 and aimed to enroll 372 patients into four intervention and the control arm.

Control:HRZE isoniazid, rifampicin standard, pyrazinamide, ethambutol
Arm 1 (R35):HR35ZEisoniazid, rifampicin 35 mg/kg, pyrazinamide, ethambutol
Arm 2 (Q):HRZQisoniazid, rifampicin standard, pyrazinamide, SQ109 300 mg
Arm 3 (R20Q): HR20ZQisoniazid, rifampicin 20 mg/kg, pyrazinamide, SQ109 300 mg
Arm 4 (R20M):HR20ZMisoniazid, rifampicin 20 mg/kg, pyrazinamide, moxifloxacin 400 mg

For more information on the study please see: ClinicalTrials.gov – Identifier: NCT01785186