| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| invasive fungal infections due to Lomentospora prolificans, Scedosporium spp., Aspergillus spp., and other resistant fungi |
|
| E.1.1.1 | Medical condition in easily understood language |
| invasive fungal infections |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Bacterial Infections and Mycoses [C01] |
| MedDRA Classification |
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| Describe the Data Review Committee (DRC)-adjudicated efficacy of F901318 as treatment for infections due to resistant fungi in patients lacking suitable alternative treatment options. |
|
| E.2.2 | Secondary objectives of the trial |
• Describe the safety of F901318 as treatment for infections due to Lomentospora prolificans, Scedosporium spp., Aspergillus spp., and other resistant fungi in patients lacking suitable alternative treatment options.
• Describe the efficacy of F901318 in terms of Investigator-assessed overall response (integrating clinical, radiological and mycological response).
• Describe all-cause mortality.
• Characterize pharmacokinetics (PK) of study drug and metabolite(s)
• Evaluate patient-reported outcomes based on the EQ-5D-5L questionnaire.
• Evaluate the F901318 plasma concentration-QTc relationship by
providing data from time-matched PK samples and Holter ECG recordings
(to be reported separately) |
|
| E.2.3 | Trial contains a sub-study | Yes |
| E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
| ECG Substudy Protocol Addendum |
|
| E.3 | Principal inclusion criteria |
1. Male and female patients aged at least 18 years or male and female
patients aged 16 years or 17 years and who weigh at least 40 kg who
have been fully informed and who have given voluntary written informed
consent, or whose legally authorized representative(s) have been fully
informed and have given voluntary written informed consent if
applicable and in compliance with local regulations, OR: Patients unable
to write and / or read but who fully understand the oral information
given by the Investigator who have given oral informed consent
witnessed in writing by an independent person and in compliance with
local regulations.
2. Ability and willingness to comply with the protocol.
3.Female patients must be non-lactating and at no risk of pregnancy for one of the following criteria:
a.Postmenopausal for at least 1 year;
b.Post-hysterectomy and/or post-bilateral ovariectomy;
c.Of childbearing potential, with a negative urine or serum human chorionic gonadotropin pregnancy test at the Screening visit and must be using a highly effective method of birthcontrol throughout the course of the study period:
i)Established use of oral, injected, transdermal, intravaginal or implanted hormonal methods of contraception associated with inhibition of ovulation
ii)Placement of an intrauterine device or intrauterine hormone-releasing system
iii)Male sterilisation (with the appropriate post-vasectomy documentation of the absence of sperm in the ejaculate
iv)Bilateral tubal occlusion
v)Sexual abstinence (reliable sexual abstinence is acceptable but periodic abstinence [e.g. calendar, ovulation, symptom-thermal, or post ovulation methods] and withdrawal are not acceptable)
4.Male patients with female partners of childbearing potential must either totally abstain from sexual intercourse or use a highly effective means of contraception throughout study participation and agree to continue its use for 30 days after stopping study drug.
5.Patients with one of these 4 forms of invasive fungal infection confirmed by culture or other diagnostic (as agreed with the MM):
a)Lomentospora (Scedosporium) prolificans (LoPro),
b)Scedosporium spp.,
c)spergillus spp.,
d) Other F901318-susceptible fungi (as described in the IB or based on information provided by the MM, and in either case requiring approval of the MM),
OR
e) Probable LRTD IA based on EORTC/MSG criteria (Appendix 2) but not meeting the criteria for culture proven invasive fungal infection.
*For further details on inclusion criterium 6, see the protocol footnote
6. Patients will also have limited alternative treatment options based on meeting one or more of the following criteria:
a) Known or predicted resistance of the infecting isolate to all licensed agents. LoPro automatically meets this criterion – other fungi may qualify after discussion with the MM,
b) Failure of available therapy. Failure to improve based on clinical or radiologic grounds despite receiving ≥7 days of standard antifungal treatment AND alternative licensed agents are either predicted to be ineffective or are contraindicated,
c) Intolerance to available therapy. Current therapy cannot be continued due to therapy-related adverse reactions (e.g., increase in serum creatinine above upper limit of normal with an amphotericin, persistent visual disturbances with voriconazole, allergic reaction with any compound, or other recognized drug-related AE) AND alternative licensed agents are either predicted to be ineffective or are contraindicated, d) Inability to manage DDIs. Inability to continue current therapy due to DDIs that cannot be managed AND alternative licensed agents are either predicted to be ineffective or are contraindicated,
e) Inability to produce therapeutic drug levels. Inability to produce or maintain therapeutic blood levels with current therapy AND alternative licensed agents are either predicted to be ineffective or are contraindicated
f)An IV-only option (e.g., an amphotericin) has produced a clinical response AND it is standard practice to switch to an oral azole for completion of therapy AND at least one of the following is true:
i) Azole-resistance is known based on susceptibility testing of the infecting isolate,
ii) Azole-resistance is predicted by PCR or similar molecular diagnostic tool,
iii) Azole-resistance is suspected based on epidemiological or clinical grounds (e.g., development of aspergillosis while on mould-active azole prophylaxis;history of lack of response to a mould-active azole at an early point in the therapeutic course)
iv) An azole would be acceptable therapy but it is known or predicted that unmanageable DDIs will occur
g) Other MM agreed inclusion. Patient does not meet any of criteria a) to f), but treatment with F901318 is judged appropriate by the investigator. Inclusion of patients based on this category must be agreed with the MM and the rationale must be documented. |
Inclusion Criteria for Extended Treatment Phase
1. Patient has completed 84 to 90 days of treatment with F901318 in the main study phase.
2. In the Investigator's opinion the patient has potential to continue to benefit from extended treatment with F901318. The Investigator must discuss ET with the MM, and the MM must approve ET for each patient.
3.No other alternative treatment option is available.
4. Patient is willing to give informed consent for ET.
5. Patient is willing and able to comply with monthly visits to the clinic for assessments. |
|
| E.4 | Principal exclusion criteria |
1. Women who are pregnant or breastfeeding.
2. Known history of allergy, hypersensitivity, or any serious reaction to any component of the study drug.
3. Patients with chronic aspergillosis, aspergilloma or allergic bronchopulmonary aspergillosis.
4. Suspected zygomycosis (mucormycosis) as the IFD used to quality for the study. Evidence for the presence of F901318 non-susceptible filamentous fungi such as Mucorales should be urgently followed up. Increased vigilance for the possibility of zygomycosis is required for suspected IA with negative baseline GM.
5. Microbiological findings (e.g., virological) or other potential conditions that are temporally related and suggest a different etiology for the clinical features.
6. HIV infection but not currently receiving antiretroviral therapy. In cases where HIV infection is first diagnosed at the same time as the invasive fungal infection, if antiretroviral therapy is commenced at the time of enrollment, then such patients are eligible for enrollment.
7. Any known or suspected condition of the patient that may jeopardize adherence to the protocol requirements or impede the accurate measurement of efficacy (e.g. neutropenia not expected to resolve, patients with uncontrolled malignancy who are treatment refractory and receiving only palliative therapy).
8. Patients with a concomitant medical condition that, in the opinion of the Investigator, may be an unacceptable additional risk to the patient should he / she participate in the study.
9. Patients previously enrolled in a study with F901318.
10. Treatment with any investigational drug in any clinical trial within the 30 days prior to the first administration of study drug except for unblinded protocols (e.g. open-label oncological regimen variations or biologic studies). Prior to enrolling patients that are on other open label studies it is the site’s responsibility to ensure that the study criteria for that study allow for enrolment into this study.
11. Patients receiving treatment limited to supportive care due to predicted short survival time.
12. Patients with a baseline prolongation of QTcF ≥500 msec, or at high risk for QT/QTc prolongation, e.g.a) A family history of long QT syndrome
b) Other known pro-arrhythmic conditions
c) Risk factors for Torsade de Pointes (e.g. uncompensated heart failure, abnormal plasma potassium or magnesium levels that cannot be corrected, an unstable cardiac condition during the last 30 days).
13. Evidence of hepatic dysfunction with any of the following abnormal laboratory parameters at Screening:
a) Total bilirubin ≥2 x ULN
b) Alanine transaminase or aspartate transaminase ≥3 x ULN
c) Patients with known cirrhosis or chronic hepatic failure
14. Prohibited concomitant medications. Concomitant administration of inhibitors of human DHODH (teriflunomide and leflunomide) is prohibited. There are currently no other absolutely prohibited concomitant medications but there are medications with potentially significant DDIs and the management of potential interactions should be considered before study enrolment (Section 5.9.1).
15. Additional exclusion criteria required by local regulatory authorities.
These include, but are not limited to,:
- Patients accommodated in an institution because of regulatory or legal order.
- Prisoners or subjects who are legally institutionalized.
- Patients who are not suitable for participation, whatever the reason, as judged by the Investigator, including medical or clinical conditions, or patients potentially at risk of noncompliance to study procedures.
- Patients who are dependent on the Sponsor or Investigator or who are deemed vulnerable for any reason.
- Patients who are employees of the clinical study site or other individuals directly involved in the conduct of the study, or immediate family members of such individuals.
- Any specific situations during study implementation/course that may raise ethics consideration.
Exclusion Criteria for Extended Treatment Phase.
1. Patients who are not suitable for participation in the ET phase, whatever the reason, as judgedby the Investigator, including medical or clinical conditions, or patients potentially at risk of noncompliance to study procedures.
Patients who are unwilling or unable to continue the contraceptive measures as described for the main study phase. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
The primary efficacy endpoint is the DRC-adjudicated overall response at Day 42 as determined by an independent DRC using a combination of clinical, mycological and radiological results and will be presented overall and by each of the five DRC-adjudicated disease categories as:
• Success
• Failure (where failure includes those patients for whom data at Day 42 cannot be collected or who are considered not evaluable at Day 42)
The criteria for assessment and categorisation of the DRC-adjudicated overall response will be detailed in the DRC Charter and subsequently specified in the detailed SAP.
Patients withdrawn from study drug due to an unsuccessful overall outcome are required per protocol to return for the EOT visit but will not be asked to return for the Day 42 and/or Day 84 visits; however, these patients will be considered as failures at all subsequent timepoints. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
| E.5.2 | Secondary end point(s) |
• DRC-adjudicated overall response (overall and by DRC-adjudicated disease category) at Day 7, Day 14, Day 28 main study phase, EOT, Day 84 and 4-week FU* (as determined by an independent DRC using a combination of clinical, mycological and radiological results) categorised as:
o Success
o Failure
• Investigator-assessed overall response (overall and by DRC-adjudicated disease category as determined by investigator using all available assessment results including clinical, mycological and radiologic results) at Day 7, Day 14, Day 28, Day 42 main study phase, EOT, Day 84 and 4-week FU* will be categorized as:
o Success
o Failure (where failure includes those patients with missing responses or considered not evaluable)
• DRC-adjudicated and Investigator-assessed clinical response overall and by DRC-adjudicated disease category at Day 7, Day 14, Day 28, Day 42 main study phase, EOT, Day 84 and 4-week FU will be categorised as:
o Success (categories of Resolution-Complete and Resolution-Partial)
o Failure (categories of Failure-Stable, Failure-Progression, and Results not available)
• Where appropriate for the IFD, radiological response at Day 7, Day 14, Day 28, Day 42 main study phase, EOT, Day 84 and 4-week FU*. will be presented overall, by the 5 DRC-adjudicated disease categories and in addition by baseline susceptibility category. See Section 6.3 for further details on response definitions.
• DRC-adjudicated and Investigator-assessed mycological response at Day 7, Day 14, Day 28, Day 42 main study phase, EOT, Day 84 and 4-week FU* will be presented overall, by the five DRC-adjudicated disease categories and in addition by baseline susceptibility category based on the categorised response of:
o Success (Proven or presumed eradication)
o Failure (Persistence, presumed persistence, Recurrent or emergent infection or any other response except proven or presumed eradication)
• All-cause mortality rate will be summarised overall and by each of the five DRC-adjudicated disease categories at Day 42 main study phase, EOT, Day 84 and 4-week FU*. In addition, overall survival (median time to death) will be presented.
Patients with complete clinical response to study drug treatment will
also be evaluated for relapse of the treated IFD and for newly emergent
IFD at selected study visits up to the main study phase EOT visit (Day 84
to Day 90).
If deemed relevant, the aforementioned endpoints may also be summarised by subgroups judged relevant (e.g., the subgroup of subjects who continued therapy beyond Day 90 and who thus have only a single combined EOT visit encompassing Day 84 and EOT)
*Change from baseline during treatment in ECG measured by Holter
monitor in a subset of patient (to be reported separately)
*For patients planning to receive ET beyond Day 90, the Day 84 visit and the main study phase EOT visit will be combined into a single Day 84 / EOS / EOT visit on approximately Day 90 and there will be no 4-week FU visit in the main study phase. |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| Day 7, Day 14, Day 28, Day 42 main study phase, EOT, Day 84 and 4-week FU |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | No |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | Yes |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | No |
| E.8.1.1 | Randomised | No |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | Yes |
| E.8.1.7.1 | Other trial design description |
|
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | Information not present in EudraCT |
| E.8.2.2 | Placebo | Information not present in EudraCT |
| E.8.2.3 | Other | Information not present in EudraCT |
| E.8.2.4 | Number of treatment arms in the trial | 1 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 3 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 19 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| Argentina |
| Australia |
| Brazil |
| Egypt |
| Israel |
| Korea, Republic of |
| Russian Federation |
| Thailand |
| United States |
| Belgium |
| France |
| Germany |
| United Kingdom |
| Netherlands |
| Spain |
|
| E.8.7 | Trial has a data monitoring committee | Yes |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | |
| E.8.9.1 | In the Member State concerned months | 57 |
| E.8.9.1 | In the Member State concerned days | 7 |
| E.8.9.2 | In all countries concerned by the trial months | 60 |
Print
