The aim of this trial is to test in a first clinical study the above mentioned hypothesis that BAY63-2521 can at least partially correct deltaF508-CFTR function. Therefore, we plan to include patients with Cystic Fibrosis, who are homozygous for the…
ID
Source
Brief title
Condition
- Congenital and hereditary disorders NEC
- Congenital respiratory tract disorders
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
To assess the safety and tolerability of oral administration of
BAY63-2521versus placebo in homozygous deltaF508 Cystic Fibrosis patients
To assess early signs of efficacy of BAY63-2521 versus placebo in homozygous
deltaF508 Cystic Fibrosis patients as observed by change from baseline in sweat
chloride content
Secondary outcome
To assess early signs of efficacy of BAY63-2521 versus placebo in homozygous
deltaF508 Cystic Fibrosis patients as observed by change from baseline in nasal
potential difference (NPD), lung clearance index (LCI) and forced expiratory
volume in 1 second (FEV1)
To assess the pharmacokinetics (PK) of BAY63-2521 and its main metabolite M1
(BAY60 4552) in homozygous deltaF508 Cystic Fibrosis patients
Additional objective is to evaluate further biomarkers to investigate the drug
(i.e. mode-of-action-related effect and/or safety) and/or the pathomechanism of
the disease.
Background summary
Cystic Fibrosis, also termed as mucoviscidosis, is one of the most prevalent
genetic disorders. Cystic Fibrosis is an autosomal recessive inherited disease
and is affecting 1 out of 2,500 to 3,000 newborns with a prevalence of around
60,000 to 70,000 patients worldwide. Cystic Fibrosis patients have a
substantially reduced quality of life, facing high morbidity and mortality with
an overall survival age of only 40 years. Cystic
Fibrosis is caused by several mutations of a single gene, the Cystic Fibrosis
transmembrane conductance regulator (CFTR) gene, which encodes for a chloride
ion channel. There are different mutations of the CFTR gene characterized,
however approximately 80-90% of Cystic Fibrosis patients are carrying the
deltaF508- mutation, a deletion of phenylalanine (F) in position 508 of the
CFTR channel. The deletion of residue 508 in deltaF508 CFTR prevents the mature
protein from correct processing and folding. This misfolded CFTR is degraded
and cannot, or cannot completely, exit the endoplasmatic reticulum and traffic
to the plasma membrane. The reduced number of channels (and associated
reduction in ion channel activity) finally leads to a substantial reduction of
the airway surface liquid layer. Under these conditions the mucus becomes
dehydrated, viscous and can no longer be cleared by cilia. Reduction of
mucociliary clearance results in chronic inflammation and infection of the
lungs and a progressive decline of lung function. Therefore, correction and
potentiation of the CFTR channel
function, which is the basal defect, could become a disease modifying treatment
option in Cystic Fibrosis with significant impact.
Currently, only two disease modifying therapies are available. Ivacaftor
(VX-770, Kalydeco), a CFTR channel potentiator, is approved for patients with
the G551D - mutation, which comprise about 4% of the total patient population,
and for a few other rare (gating) mutations. In July 2015, Ivacaftor+Lumacaftor
(Orkambi), a therapy combining a CFTR channel potentiator with a CFTR channel
corrector (Lumacaftor) has been approved by US FDA for patients homozygous for
the DF508 mutation.For the vast majority, no disease modifying therapy is
available.
Riociguat is approved in the United States and Canada for chronic
thromboembolic pulmonary hypertension (CTEPH) and pulmonary arterial
hypertension (PAH) under the trade name Adempas. Preclinical data indicate that
BAY63-2521 (Riociguat) might be able to act as a disease modifier by correcting
deltaF508-CFTR function. The magnitude of effects observed with sGC stimulators
in preclinical models may translate in a significant clinical benefit in Cystic
Fibrosis patients. BAY63-2521 (Riociguat) has already been tested in healthy
volunteers and patients with
pulmonary arterial hypertension and chronic thromboembolic pulmonary
hypertension. Clinical results showed that Riociguat was e.g. able to improve
the 6- minute walk distance and exercise capacity in patients with pulmonary
arterial hypertension. A positive risk-benefit assessment has been established
in these two indications.
Study objective
The aim of this trial is to test in a first clinical study the above mentioned
hypothesis that BAY63-2521 can at least partially correct deltaF508-CFTR
function. Therefore, we plan to include patients with Cystic Fibrosis, who are
homozygous for the deltaF508-CFTR
mutation.
Parameters, which are considered to reflect CFTR function (sweat chloride test
and NPD) and different aspects of lung function (lung clearance index [LCI] and
FEV1), will be used as read outs for pharmacodynamics effects (signs of
efficacy, surrogate efficacy marker). As this is a first *early signs of
efficacy* study, the study has been powered for the primary endpoint *change in
sweat chloride content compared to baseline* only.
An additional aim is to evaluate the pharmacokinetic (PK) properties of
BAY63-2521 in these patients in order to allow for investigation of
pharmacokinetic/ pharmacodynamics (PK/ PD)-relationship and appropriate dose
finding studies in later stages of clinical development.
Treatment doses in this study have been selected based on the experience in
earlier studies in the above mentioned indications PAH and CTEPH.
Study design
This study is a phase 2, randomized, double-blind, placebo-controlled,
sequential group, multi-center, international study designed to investigate
safety, tolerability, early signs of efficacy and PK of BAY63-2521 in adult
Cystic Fibrosis patients.
Intervention
The study will consist of part 1 and 2.
In the first part patients will be randomized using a 1-to-2 randomization to
either placebo or one treatment arm (= lower dose cohort). Within the placebo
arm only placebo will be given. Within the active treatment arm, patients will
start on 0.5 mg BAY63-2521 for 14 days. The dose will be increased to 1 mg
BAY63 2521 for an additional 14 days, if this is considered safe and tolerable
on the basis of the available data for a given patient.
After all patients of part 1 have finished the treatment period, an independent
Data Safety Monitoring Board (DSMB) will decide * based on safety and
tolerability data - whether the second part of the trial can be started.
In the second part a second cohort of patients will be randomized using a
1-to-2 randomization to either placebo or one treatment arm (= higher dose
cohort). Within the placebo arm only placebo will be given. Within the active
treatment arm patients will start on 1 mg BAY63-2521 for 14 days. The dose will
be increased to 2 mg BAY63 2521 for an additional 14 days, if this is
considered safe and tolerable on the basis of the available data for a given
patient.
For all patients the first two intakes of study medication will take place at
the study site for safety reasons. The patient will be discharged after a
safety monitoring period of four hours after the second intake. The same
precautions will apply at Visit 6 when the dose is planned to be increased.
Study burden and risks
The study involves 7 visits to the study center and two telephone calls and the
patients will take part in the study for maximum 9 weeks. The two visits
where the study medication is given for the first time (visit 3) or up-titrated
(visit 6) will require a stay at the study center for at least 12,5 hours. For
the other visits a duration of 3-4 hours is estimated. At the visits
measurements of NPD (optional), LCI and FEV1 will be performed as well as blood
pressure, heart rate be monitored, blood samples taken (not more than 300 mL,
i.e. approx. 21 table spoons over the whole study), oxygen concentration
measured and sweat tests performed. Additionally, patients will be asked to
complete a Cystic Fibrosis Questionnaire about their quality of life and to
document the intake of the study medication in a paper diary.
An overview of all study visits and all related study procedures can be found
in the protocol in table 14-1, 14-2, 14-3 and 14-4. A description of all study
procedures is written in section 7 of the protocol.
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Leverkusen 51368
DE
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Leverkusen 51368
DE
Listed location countries
Age
Inclusion criteria
1. Signed informed consent available before any study specific tests or procedures are performed
2. Patients must be at least 18 years of age at time of inclusion (i.e. upon signature of informed consent)
3. Patient diagnosed with Cystic Fibrosis according to standard criteria (i.e. either
elevated sweat chloride content above 60 mmol/ L and/ or genetic testing)
4. Patient is homozygous for the deltaF508 mutation
5. Patient has a mild-to-moderate stage of lung disease as determined by FEV1
(FEV1 between 40 and 100% predicted)
6. Patient has a stable condition of lung disease (no ongoing or recent pulmonary exacerbation and no change in current treatment) within the last 4 weeks prior to screening
7. Ability and willingness to understand and follow study procedures for the entire Study
8. Patients do not smoke. Patients with a history of smoking can be included, if they
have refrained from smoking for the last 3 months. If a patients starts smoking
during the study participation, he/ she needs to be excluded and considered to be a
drop-out
9. Body mass index (BMI): * 16 and * 32 kg/ m² (calculated by dividing the patient*s weight by the square of his/ her height [kg/ m2])
10. Women of childbearing potential must agree to use adequate contraception when sexually active. *Adequate contraception* is defined as one highly effective form of contraception (intrauterine devices [IUD], contraceptive implants or tubal sterilization) or a combination of methods (hormone method with a barrier method). If a partner*s vasectomy is the chosen method of contraception or if a partner has documented azoospermia, a hormone or barrier method must be used in combination. Adequate contraception is required from the
signing of the informed consent form up until 4 weeks after the last study drug administration.
Exclusion criteria
1. Patients with Cystic Fibrosis with any background other than homozygous deltaF508
mutation
2. Patients receiving treatment with Ivacaftor
3. Active state of hemoptysis or pulmonary hemorrhage, including those events
managed by bronchial artery embolization. Also any history of moderate hemoptysis
within the 3 months prior to inclusion
4. Any history of pneumothorax, bronchial artery embolization or massive hemoptysis.
Massive hemoptysis being defined as acute bleeding >240 mL in a 24-hour period or
recurrent bleeding >100 mL/ d over several days
5. A positive sputum culture for Burkholderia cenocepacia, Burkholderia dolosa, and/
or Mycobacterium absessus either currently or within the previous year.
6. Active allergic broncho-pulmonary aspergillosis
7. Current pulmonary exacerbation
8. Known history of solid organ transplantation
9. Known history of any form of pulmonary arterial hypertension;11. Known or suspected malignant tumors or a history of malignant tumors
12. Unstable liver disease as indicated by
a. bilirubin >2 times upper limit normal (ULN) and/ or hepatic transaminases >5
times ULN
b. signs of severe hepatic insufficiency (e.g. impaired albumin synthesis with an
albumin < 32g/ L, hepatic encephalopathy > Grade 1a)
13. Patients with severe hepatic impairment (Child Pugh C) should be excluded
14. Recent evidence (within 12 months prior to inclusion) of distal intestinal obstruction
syndrome.
15. Patients with creatinine clearance <15 mL/ min or on dialysis need to be excluded.
16. Known history of cardiovascular disease unless stable and without therapy changes in
the previous 3 months
17. Known history of clinically relevant arterial hypotension or clinically relevant
orthostatic reactions (e.g. as indicated by syncopes, dizziness)
18. Venous/ arterial thromboembolic diseases (particularly deep vein thrombosis,
pulmonary embolism, stroke, myocardial infarction)
19. Known current thyroid disorders which require treatment (patients with an euthyroid
struma who do not need any treatment can participate)
20. Known hypersensitivity to the study medication (active substances or excipients of
the preparations)
21. Documented severe or clinically significant allergic reactions including anaphylaxis
or hives
22. Intolerance to lactose requiring strictly lactose-free diet and restriction to lactose-free
oral medicines (hereditary galactose intolerance, galactose-glucose malabsorption,
lactase deficiency)
23. Recent history (i.e. in the last 12 months prior to screening) of severe hypoglycemic
events in patients with severe Cystic Fibrosis diabetes
24. Any medical disorder, condition, or history of such that would impair the patient's
ability to participate or complete this study in the opinion of the investigator
25. Smoking (former smokers who have stopped smoking at least 3 months prior to the
first screening visit may be included)
26. Suspicion of drug or alcohol abuse or recent (i.e. within 2 years) history of drug,
medicine or alcohol abuse
27. Donation of blood or plasmapheresis after or within 4 weeks of signing the informed
consent form
28. Concomitant use of the following medication: nitrates or nitric oxide donors (such as
amyl nitrite) in any form, PDE 5 inhibitors (such as sildenafil, tadalafil, vardenafil),
strong multi pathway CYP and p-gp/ BCRP inhibitors such as azole antimycotics (e.g.
ketoconazole, itraconazole) or HIV protease inhibitors (e.g. ritonavir).
29. Clinically relevant ECG findings in screening ECG
30. Systolic blood pressure below 95 or above 160 mmHg (after at least 10 min in supine
position) at screening
31. Diastolic blood pressure below 50 or above 100 mmHg (after at least 10 min in supine
position) at screening
32. Heart rate below 45 or above 100 beats/ min (after at least 10 min in supine position)
at screening
33. Clinically relevant findings in the physical examination, which in the opinion of the
investigator prevents patients from safe participation in the study
34. Positive urine pregnancy test
35. Positive cotinine test in conjunction with current tobacco smoking. In case cotinine
positivity refers to oral/nasal nicotine consumption only and current smoking is
excluded, the patient may be enrolled.
36. Positive results for hepatitis B virus surface antigen (HBsAg), hepatitis C virus
(HCV) antibodies, anti- or human immune deficiency virus (HIV 1+2) antibodies
37. Clinically relevant deviations of the screened laboratory parameters from reference
ranges outside of expected changes for Cystic Fibrosis patients, especially a
hemoglobin value below 110 g/L or a creatinine clearance based on the Cockcroft-Gault formula < 15 ml/ min
38. Pregnant women (i.e. positive pregnancy test or other signs of pregnancy), or breast
feeding women
39. Patient is in custody by order of an authority or a court of law
40. Exclusion periods from other studies or simultaneous participation in other clinical
studies/ participation in another clinical study during the preceding 6 weeks (i.e. last
treatment from previous study to first treatment of new study)
41. Previous assignment to treatment (e.g. randomization) during this study (allowing
previously randomized patients to be re-included into the study may lead to bias)
42. Close affiliation with the investigational site (e.g. a close relative) or persons working
at the study site
43. Patient is an employee of Bayer HealthCare or Bayer Pharma AG or of Theorem CR
(the acting contract research organization)
44. Criteria which in the opinion of the investigator preclude participation for scientific
reasons, for reasons of compliance, or for reasons of the patient*s safety.
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| EudraCT | EUCTR2013-004595-35-NL |
| ClinicalTrials.gov | NCT02170025 |
| CCMO | NL53573.078.15 |