Clinical Trials Register

Summary
EudraCT Number:	2020-002059-38
Sponsor's Protocol Code Number:	APRIL
National Competent Authority:	Germany - BfArM
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2020-12-30
Trial results	View results

Index
A. PROTOCOL INFORMATION
B. SPONSOR INFORMATION
C. APPLICANT IDENTIFICATION
D. IMP IDENTIFICATION
D.8 INFORMATION ON PLACEBO
E. GENERAL INFORMATION ON THE TRIAL
F. POPULATION OF TRIAL SUBJECTS
G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
P. END OF TRIAL

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A. Protocol Information

A.1

Member State Concerned

Germany - BfArM

A.2

EudraCT number

2020-002059-38

A.3

Full title of the trial

A Double-Blind, Placebo-Controlled, Randomized, Phase Ib/IIa Clinical Study of ApTOLL for the Treatment of Acute Ischemic Stroke

A.3.1

Title of the trial for lay people, in easily understood, i.e. non-technical, language

A Double-Blind, Placebo-Controlled, Randomized, Phase Ib/IIa Clinical Study of ApTOLL for the Treatment of Acute Ischemic Stroke

A.4.1

Sponsor's protocol code number

APRIL

A.5.2

US NCT (ClinicalTrials.gov registry) number

NCT04734548

A.7

Trial is part of a Paediatric Investigation Plan

A.8

EMA Decision number of Paediatric Investigation Plan

B. Sponsor Information
B.Sponsor: 1
B.1.1	Name of Sponsor	APTATARGETS S.L.
B.1.3.4	Country	Spain
B.3.1 and B.3.2	Status of the sponsor	Commercial
B.4 Source(s) of Monetary or Material Support for the clinical trial:
B.4.1	Name of organisation providing support	Aptatargets
B.4.2	Country	Spain
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	ANAGRAM-ESIC
B.5.2	Functional name of contact point	Clinical Operations
B.5.3	Address:
B.5.3.1	Street Address	c/Esteve Terradas, 37-41
B.5.3.2	Town/ city	Barcelona
B.5.3.3	Post code	08023
B.5.3.4	Country	Spain
B.5.4	Telephone number	34934515250
B.5.5	Fax number	34937509134
B.5.6	E-mail	s.casellas@angram-esic.com

D. IMP Identification
D.IMP: 1
D.1.2 and D.1.3	IMP Role	Test
D.2	Status of the IMP to be used in the clinical trial
D.2.1	IMP to be used in the trial has a marketing authorisation	No
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	No
D.2.5.1	Orphan drug designation number
D.3 Description of the IMP
D.3.1	Product name	Aptoll
D.3.2	Product code	Aptamer 4FT
D.3.4	Pharmaceutical form	Powder for concentrate for solution for infusion
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Intravenous use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	Non established
D.3.9.2	Current sponsor code	ApTOLL
D.3.9.3	Other descriptive name	APTAMER 4FT
D.3.9.4	EV Substance Code	SUB192732
D.3.10	Strength
D.3.10.1	Concentration unit	mg milligram(s)
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	7
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	Yes
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	No
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	No
D.3.11.3.1	Somatic cell therapy medicinal product	No
D.3.11.3.2	Gene therapy medical product	No
D.3.11.3.3	Tissue Engineered Product	No
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	No
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	No
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	No
D.3.11.5	Radiopharmaceutical medicinal product	No
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	No
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	No
D.3.11.10	Medicinal product containing genetically modified organisms	No
D.3.11.11	Herbal medicinal product	No
D.3.11.12	Homeopathic medicinal product	No
D.3.11.13	Another type of medicinal product	No

D.8 Information on Placebo
D.8 Placebo: 1
D.8.1	Is a Placebo used in this Trial?	Yes
D.8.3	Pharmaceutical form of the placebo	Powder for concentrate for solution for infusion
D.8.4	Route of administration of the placebo	Intravenous use

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

Acute Ischemic Stroke (AIS)

E.1.1.1

Medical condition in easily understood language

Stroke

E.1.1.2

Therapeutic area

Diseases [C] - Nervous System Diseases [C10]

MedDRA Classification

E.1.3

Condition being studied is a rare disease

E.2 Objective of the trial

E.2.1

Main objective of the trial

To evaluate if administration of ApTOLL intravenously (i.v.) at different doses is safe and well tolerated compared to placebo when administered with endovascular therapy (EVT)± i.v. rt-PA in the AIS target population.

E.2.2

Secondary objectives of the trial

Phase Ib:
1. To determine the pharmacokinetic (PK) profile of ApTOLL in AIS patients, evaluated by the determination of ApTOLL levels in plasma and urine.
2. To select the two doses to be administered in Phase IIa according to their safety profile.
3. To provide an initial estimate of the biological effect of ApTOLL on the final infarct volume (measured by MRI- FLAIR at 72±24 hours) and on pro-inflammatory biomarkers linked to AIS (baseline, and 1h, 6h, 24h, 48h and 72h post-dose).
Phase IIa:
1. To assess the biological effect of ApTOLL on the final infarct volume (measured by MRI-FLAIR at 72±24 hours) and on pro-inflammatory biomarkers linked to AIS (at predose, and at 6h, 24h, 48h and72h post-dose).
2. To determine the biological effect of ApTOLL as measured by the residual functional impairment after AIS (NIHSS at 72h or discharge (whatever occurs first) and modified Ranking Score (mRS) at 90d post stroke).

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1. Age ≥18 and ≤85 years.
2. Informed consent obtained from subject or acceptable subject surrogate (i.e. next of kin, or legal representative).
3. A new focal disabling neurologic deficit consistent with acute cerebral ischemia.
4. Baseline NIHSS obtained prior to randomization ≥ 8 points and ≤ 25 points.
5. Pre-stroke mRS score of 0 - 2.
6. Treatable as soon as possible and at least within 6 h of symptom onset, defined as point in time when the subject was last seen well (at baseline). (Treatment start is defined as study drug administration).
7. Patients should be candidates to receive EVT treatment with or without i.v. rt-PA. For such patients candidates to i.v. rt-PA therapy, rt-PA should be initiated as recommended by the European Stroke Organization for the early management of patients with AIS, it means, as soon as possible and within 4.5h of stroke onset (onset time is defined as the last time when the patient was witnessed to be well at baseline), with investigator verification that the subject has received/is receiving the correct i.v. rt-PA dose for the estimated weight. Should for any reason i.v. rt-PA is prematurely halted the cause and the total administered dose will be recorded. On the other hand, once the patient is included in the study, if it is observed and documented that recanalization has occurred, the patient will continue in the trial and no protocol deviation will be recorded.
Neuro Imaging:
8. Occlusion (TICI 0 or TICI 1 flow), of the terminal internal carotid artery (TICA), M1 or M2 segments of the middle cerebral artery, suitable for mechanical thrombectomy, confirmed on CTA (CT Angiography). Tandem extra-intracranial lesions may be included.
9. The following imaging criteria should also be met on admission neuroimaging:
a) MRI criterion: volume of DWI (Diffusion-weighted Imaging) restriction ≥5 mL and ≤70 mL determined by RAPID® software OR.
b) CT criterion: Alberta Stroke program early CT score (ASPECTS) 6 to 10 on baseline CT AND infarct core determined on admission CTPerfusion by CBF≥30%: ≥5 mL and ≤70 mL determined by RAPID® software.
NOTE: ASPECTS will be stablished following the investigator criterium.
10. The subject has an indication and is planned to receive endovascular treatment of stroke according to the ESO Guidelines.

E.4

Principal exclusion criteria

1. Subject has suffered a stroke in the past 1 year.
2. Occlusion (TICI 0 or TICI 1 flow) of the basilar or vertebral or posterior or anterior cerebral arteries.
3. Clinical symptoms suggestive of bilateral stroke or stroke in multiple territories.
4. Known hemorrhagic diathesis, coagulation factor deficiency, or oral anticoagulant therapy with INR >3.0.
5. Baseline platelet count <50,000/μL.
6. Baseline blood glucose of <50 mg/dL or >400 mg/dL.
7. Severe, sustained hypertension (systolic blood pressure >185 mmHg or diastolic blood pressure >110 mmHg).
NOTE: If the blood pressure can be successfully reduced and maintained at an acceptable level using European Stroke Organization (ESO) guidelines recommended medication (including i.v. antihypertensive drips), the patient can be enrolled.
8. Serious, advanced, or terminal illness with anticipated life expectancy of less than 1 year.
9. Subjects with identifiable intracerebral tumors (meningioma is considered extracerebral tumor, so it is not included in this exclusion criterium).
10. History of life-thratening allergy (more than rash) to contrast medium.
11. Known renal insufficiency with creatinine ≥3 mg/dL or Glomerular Filtration Rate (GFR) <30 mL/min.
12. Cerebral vasculitis.
13. Evidence of active systemic infection.
14. Known current use of cocaine at time of treatment.
15. Patient participating in a study involving an investigational drug or device that would impact this study.
16. Patients that are unlikely to be available for a 90-day follow-up (e.g. no fixed home address, visitor from overseas).
17. Female who is pregnant or lactating or has a positive pregnancy test at time of admission.
Neuro Imaging:
18. CT or MRI evidence of hemorrhage (the presence of microbleeds is allowed).
19. Significant mass effect with midline shift.
20. Suspicion of aortic dissection presumed septic embolus, or suspicion of bacterial endocarditis

E.5 End points

E.5.1

Primary end point(s)

1. Death.
2. Adverse events that occur during the study.
3. Physical examination.
4. Laboratory tests.
5. Recurrent stroke.
6. Symptomatic intracranial hemorrhage (sICH).

E.5.1.1

Timepoint(s) of evaluation of this end point

Fase Ib – 4 months after inclusion of last patient from phase Ib
Fase IIa - 4 months after inclusion of last patient from phase IIa

E.5.2

Secondary end point(s)

1. Mean final infarct volumes measured at 72± 24h (MRI: Magnetic Resonance Image). In those cases where the MRI at 72± 24h is missed, the last CT (Computed Tomography) data available after ApTOLL administration should be considered.
2. Proinflammatory markers in blood between study groups.
3. Early clinical course (NIHSS, 72h).
4. Long-term outcome (mRS, 90d). In those cases where the mRS 90 days is missed, the worst score (mRS of 6) will be assigned in case the living status of the patient is not known. For patients known to be alive at 3 months post randomization in whom follow-up evaluations will not be possible the discharge mRS will be carried forward

E.5.2.1

Timepoint(s) of evaluation of this end point

Fase Ib – 4 months after inclusion of last patient from phase Ib
Fase IIa - 4 months after inclusion of last patient from phase IIa

E.6 and E.7 Scope of the trial

E.6

Scope of the trial

E.6.1

Diagnosis

E.6.2

Prophylaxis

E.6.3

Therapy

E.6.4

Safety

Yes

E.6.5

Efficacy

Yes

E.6.6

Pharmacokinetic

Yes

E.6.7

Pharmacodynamic

E.6.8

Bioequivalence

E.6.9

Dose response

E.6.10

Pharmacogenetic

E.6.11

Pharmacogenomic

E.6.12

Pharmacoeconomic

E.6.13

Others

E.7

Trial type and phase

E.7.1

Human pharmacology (Phase I)

Yes

E.7.1.1

First administration to humans

E.7.1.2

Bioequivalence study

E.7.1.3

Other

Yes

E.7.1.3.1

Other trial type description

IIa for Germany

E.7.2

Therapeutic exploratory (Phase II)

Yes

E.7.3

Therapeutic confirmatory (Phase III)

E.7.4

Therapeutic use (Phase IV)

E.8 Design of the trial

E.8.1

Controlled

Yes

E.8.1.1

Randomised

Yes

E.8.1.2

Open

E.8.1.3

Single blind

E.8.1.4

Double blind

Yes

E.8.1.5

Parallel group

E.8.1.6

Cross over

E.8.1.7

Other

E.8.2

Comparator of controlled trial

E.8.2.1

Other medicinal product(s)

E.8.2.2

Placebo

Yes

E.8.2.3

Other

E.8.2.4

Number of treatment arms in the trial

E.8.3

The trial involves single site in the Member State concerned

Yes

E.8.4

The trial involves multiple sites in the Member State concerned

E.8.5

The trial involves multiple Member States

Yes

E.8.5.1

Number of sites anticipated in the EEA

E.8.6 Trial involving sites outside the EEA

E.8.6.1

Trial being conducted both within and outside the EEA

E.8.6.2

Trial being conducted completely outside of the EEA

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

LVLS

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

E.8.9.1

In the Member State concerned days

E.8.9.2

In all countries concerned by the trial years

F. Population of Trial Subjects

F.1 Age Range

F.1.1

Trial has subjects under 18

F.1.1.1

In Utero

F.1.1.2

Preterm newborn infants (up to gestational age < 37 weeks)

F.1.1.3

Newborns (0-27 days)

F.1.1.4

Infants and toddlers (28 days-23 months)

F.1.1.5

Children (2-11years)

F.1.1.6

Adolescents (12-17 years)

F.1.2

Adults (18-64 years)

Yes

F.1.2.1

Number of subjects for this age range:

F.1.3

Elderly (>=65 years)

Yes

F.1.3.1

Number of subjects for this age range:

121

F.2 Gender

F.2.1

Female

Yes

F.2.2

Male

Yes

F.3 Group of trial subjects

F.3.1

Healthy volunteers

F.3.2

Patients

Yes

F.3.3

Specific vulnerable populations

Yes

F.3.3.1

Women of childbearing potential not using contraception

F.3.3.2

Women of child-bearing potential using contraception

Yes

F.3.3.3

Pregnant women

F.3.3.4

Nursing women

F.3.3.5

Emergency situation

Yes

F.3.3.6

Subjects incapable of giving consent personally

Yes

F.3.3.6.1

Details of subjects incapable of giving consent

Patients may not be able to provide consent at study entry depending on the stroke severity, if so, a relative or legal representative should cosent on behalf of the patient. When possible, the patient will re-consent afterwards.

Los pacientes pueden no ser capaces de firmar el consentimiento dependiendo de la severidad del ictus.En esos casos un familiar o el representante legal firmará en lugar del paciente. Cuando sea posible el paciente dará su consentimiento más adelante

F.3.3.7

Others

F.4 Planned number of subjects to be included

F.4.1

In the member state

F.4.2

For a multinational trial

F.4.2.1

In the EEA

151

F.4.2.2

In the whole clinical trial

151

F.5

Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)

the standard of care for this type of patients

el habitual para este tipo de pacientes

G. Investigator Networks to be involved in the Trial

N. Review by the Competent Authority or Ethics Committee in the country concerned

Competent Authority Decision

Authorised

Date of Competent Authority Decision

2021-04-14

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2021-04-07

P. End of Trial
P.	End of Trial Status	Completed
P.	Date of the global end of the trial	2022-07-25

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