Clinical Trials Register

Summary
EudraCT Number:	2018-002130-20
Sponsor's Protocol Code Number:	1.4
National Competent Authority:	UK - MHRA
Clinical Trial Type:	EEA CTA
Trial Status:	GB - no longer in EU/EEA
Date on which this record was first entered in the EudraCT database:	2019-06-19
Trial 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

UK - MHRA

A.2

EudraCT number

2018-002130-20

A.3

Full title of the trial

Research on Efficacy of Teriparatide use in the Return of recruits to Normal duty.

A.3.1

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

Study of Teriparatide in Stress Fracture Healing: RETURN

A.3.2

Name or abbreviated title of the trial where available

Study of Teriparatide in Stress Fracture Healing: RETURN

A.4.1

Sponsor's protocol code number

1.4

A.5.4

Other Identifiers

Name:

EudraCT

Number:

2018-002130-20

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	Norfolk and Norwich University Hospitals NHS Foundation Trust
B.1.3.4	Country	United Kingdom
B.3.1 and B.3.2	Status of the sponsor	Non-Commercial
B.4 Source(s) of Monetary or Material Support for the clinical trial:
B.4.1	Name of organisation providing support
B.4.2	Country
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Norwich Clinical Trials Unit
B.5.2	Functional name of contact point	Ann Marie Swart
B.5.3	Address:
B.5.3.1	Street Address	University of East Anglia
B.5.3.2	Town/ city	Norwich
B.5.3.3	Post code	NR4 7TJ
B.5.3.4	Country	United Kingdom
B.5.4	Telephone number	01603597306
B.5.6	E-mail	a.swart@uea.ac.uk

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	Yes
D.2.1.1.1	Trade name	Terrosa
D.2.1.1.2	Name of the Marketing Authorisation holder	Gedeon Richter Plc
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	Terrosa
D.3.4	Pharmaceutical form	Suspension for injection in cartridge
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Subcutaneous use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	Teriparatide
D.3.9.4	EV Substance Code	AS1
D.3.10	Strength
D.3.10.1	Concentration unit	µg/ml microgram(s)/millilitre
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	250
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	No
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	Yes
	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	Yes
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.IMP: 2
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	Yes
D.2.1.1.1	Trade name	FORSTEO
D.2.1.1.2	Name of the Marketing Authorisation holder	Eli Lilly Nederland B.V.
D.2.1.2	Country which granted the Marketing Authorisation	Netherlands
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	FORSTEO
D.3.4	Pharmaceutical form	Solution for injection in pre-filled pen
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Subcutaneous use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	Teriparatide
D.3.9.4	EV Substance Code	AS2
D.3.10	Strength
D.3.10.1	Concentration unit	µg/µl microgram(s)/microlitre
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	250
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	No
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	Yes
	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	Yes
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	Solution for injection in pre-filled pen
D.8.4	Route of administration of the placebo	Subcutaneous use

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

Healthy individuals with stress fractures.

E.1.1.1

Medical condition in easily understood language

Healthy individuals with stress fractures.

E.1.1.2

Therapeutic area

Body processes [G] - Bones and nerves physological processes [G11]

MedDRA Classification

E.1.2 Medical condition or disease under investigation

E.1.2	Version	20.1
E.1.2	Level	PT
E.1.2	Classification code	10042212
E.1.2	Term	Stress fracture
E.1.2	System Organ Class	10022117 - Injury, poisoning and procedural complications

E.1.2 Medical condition or disease under investigation

E.1.2	Version	20.1
E.1.2	Level	PT
E.1.2	Classification code	10042212
E.1.2	Term	Stress fracture
E.1.2	System Organ Class	10022117 - Injury, poisoning and procedural complications

E.1.3

Condition being studied is a rare disease

E.2 Objective of the trial

E.2.1

Main objective of the trial

The primary outcome for the trial will be the improvement in radiological healing by 2 grades or more, ‘or complete healing’, indicated by a grade of zero, at 8 weeks post-randomisation.

Assessed by MRI using the modified Fredericson Stress Fracture Grading System High-Signal Short TI Inversion Recovery (STIR) Image.

E.2.2

Secondary objectives of the trial

The secondary outcomes will be as follows:

-Does PTH reduce the time to radiological healing (as assessed by MRI scanning at weeks 8, 10, 12, 14 and 16 (five in total)).
* Where participants are still assessed as not clinically healed, the treatment phase will be extended to 6-months, necessitating 2 further scans at weeks 20 and 24. These participants will therefore undergo a maximum of 7 MRI scans in total.

This may be extended to 7 scans in total however,

-Proportion assessed as ‘Clinically Healed’. Clinical assessments will be carried out twice a week at ITC(C) following an MRI grade 0 by a local researcher.

- Healing as a composite assessment of healing by MRI and clinical assessment.

- Time from randomisation to discharge from rehabilitation. Completion of rehabilitation will be assessed using Army standard measures.

- Pain symptoms using a visual analogue pain scale in a diary to be completed weekly and analysed as a change from baseline to 16 weeks (24 weeks in an unh

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1) Signed informed consent and able to comply with protocol;
2) Aged 18 to 40 years;
3) Lower limb stress fracture, confirmed by MRI scan;
4) Undergoing phase 1 or 2 training within an Army training establishment;
5) Baseline blood tests within reference range (see table 3 for more details). Minor abnormalities will be assessed by the PI. Patients will still be eligible if these are felt to be of no clinical importance and this decision is documented by the PI;
6) Participant is able to adhere to visit requirements.

E.4

Principal exclusion criteria

1) Hypersensitivity to the active Parathyroid Hormone substance or any of the excipients listed in the SPC.
2) Pre-existing hypercalcaemia
3) Patients with skeletal malignancies or bone metastases.
4) Any contraindications that would prevent the participant from undergoing an MRI scan.
5) Concurrent therapy that, in the investigators opinion, would interfere with the evaluation of the safety or efficacy of the study medication.
6) Pregnancy, suspected pregnancy or breastfeeding. Female participants must have a negative serum pregnancy test at screening and be willing and able to use a birth control method which may be considered as “highly effective”, as per the Clinical Trial Facilitation Group (CTFG) guidance.*
7) Severe renal impairment. Participants with moderate renal impairment will be treated with caution at the Principal Investigator’s discretion and in accordance with the SmPC.
8) Metabolic bone diseases including hyperparathyroidism and Paget's disease of the bone.
9) Unexplained elevations of alkaline phosphatase.
10) Prior external beam or implant radiation therapy to the skeleton.
11) Patients participating in a concurrent drug trial.
12) Presentation with open epiphyses during the diagnostic MRI scan.
13) Participants with depression, as identified by completion of the Columbia-Suicide Severity Rating Scale (C-SSRS) at Baseline.

**As per the CTFG guidance and for the purposes of this trial, a woman is considered of childbearing potential (WOCBP), i.e. fertile, following menarche and until becoming post-menopausal unless permanently sterile. Permanent sterilisation methods include hysterectomy, bilateral salpingectomy and bilateral oophorectomy. A postmenopausal state is defined as no menses for 12-months without an alternative medical cause. A high follicle stimulating hormone (FSH) level in the postmenopausal range may be used to confirm a post-menopausal state in women not using hormonal contraception or hormonal replacement therapy. However in the absence of 12 months of amenorrhea, a single FSH measurement is insufficient.

In accordance with CTFG guidance, methods that can achieve a failure rate of less than 1% per year when used consistently and correctly, are considered as “highly effective” birth control methods. Such methods include:
- Combined (estrogen and progestogen containing) hormonal contraception associated with inhibition of ovulation (either oral, intravaginal or transdermal);
- Progestogen-only hormonal contraception associated with inhibition of ovulation (either oral, injectable or implantable);
- Intrauterine device (IUD);
- Intrauterine hormone-releasing system (IUS);
- Bilateral tubal occlusion;
- Vasectomised partner;
- Sexual abstinence. (Sexual abstinence is considered a highly effective method only if defined as refraining from heterosexual intercourse during the entire period of risk associated with the study treatments. The reliability of sexual abstinence needs to be evaluated for the duration of the participant’s treatment period during the trial and the preferred and usual lifestyle of the participant.)

E.5 End points

E.5.1

Primary end point(s)

The primary outcome for the trial will be the improvement in radiological healing by 2 grades or more, ‘or complete healing’, indicated by a grade of zero, at 8 weeks post-randomisation (assessed using the modified Fredericson Stress Fracture Grading System by MRI and High-Signal Short TI Inversion Recovery (STIR) Image).

E.5.1.1

Timepoint(s) of evaluation of this end point

MRI scans will be performed at weeks 8, 10, 12, 14 and 16 (5 in total). Radiological healing will be assessed using the modified Fredericson Stress Fracture Grading System by MRI and High-Signal Short TI Inversion Recovery (STIR) Image.

E.5.2

Secondary end point(s)

Secondary outcomes will be as follows:

• Proportion assessed as ‘Clinically Healed’. Clinical assessments will be carried out twice a week at ITC(C) following an MRI grade 0 by a blinded researcher.
• Healing as a composite assessment of healing by MRI and clinical assessment.
• Time from randomisation to discharge from rehabilitation. Completion of rehabilitation will be assessed using Army standard measures.
• Pain symptoms using a visual analogue pain scale in a diary to be completed weekly and analysed as a change from baseline to 16 weeks (24 weeks in an unhealed fracture).
• Quality of life (assessed by SF36 Questionnaire) and any other appropriate questionnaires used by the army to assess readiness to return to training.
• Adverse Events including the number and severity of Adverse Reactions.

MRI scans will be performed at weeks 8, 10, 12, 14 and 16 (5 in total). Radiological healing will be assessed by MRI using the modified Fredericson Stress Fracture Grading System and High-Signal Short TI Inversion Recovery (STIR) Image.
The scale proposed by Beck et al. will be used to assess clinical healing.

Further Exploratory outcomes are as follows:

• Biochemical responses to treatment (assessed in blood and urine samples) at weeks 4, 8, 12 and 16. This will be extended to weeks 20 and 24 for participants that remain in the trial. Laboratory technicians analysing the samples will be blinded.
• Changes in bone density and micro architecture, assessed by DXA at the hip and spine between the point of randomisation and week 16, and HRpQCT at the distal radius (non-dominant arm) and distal tibia (non-fractured limb) between the point of randomisation and weeks 16 or 24. The images will be processed by by a blinded, experienced researcher.
• Differences in the physical activity levels between the treatment and control arm from the point of randomisationto week 16, or week 24 in the case of an unhealed fracture. A wrist-mounted, tri-axial accelerometer (GENEActiv, Activinsights, Kimbolton, UK) will be worn by up to 20 participants (10 in each arm) to assess physical activity throughout the trial.
• Long term future fracture rate of the treatment fracture group versus standard care will be compared at 5 years following delivery of the final report.

E.5.2.1

Timepoint(s) of evaluation of this end point

• Proportion assessed as ‘Clinically Healed’. Clinical assessments will be carried out at weeks 8, 10, 12, 14 and 16 (5 in total) in line with MRI scans and continue to weeks 20 and 24 in the case of an unhealed fracture.

• Pain symptoms using a visual analogue pain scale in a diary to be completed weekly and analysed as a change from baseline to 16 weeks (24 weeks in an unhealed fracture).

• Quality of life (assessed by SF36 Questionnaire) and any other appropriate questionnaires used by the army to assess readiness to return to training.

• Time from randomisation to assessed as ‘Clinically Healed’. Proportion assessed as ‘Clinically Healed’. Clinical assessments will be carried out every two working days following an MRI grade 0 by a blinded researcher.

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

Yes

E.6.4

Safety

Yes

E.6.5

Efficacy

Yes

E.6.6

Pharmacokinetic

E.6.7

Pharmacodynamic

E.6.8

Bioequivalence

E.6.9

Dose response

Yes

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)

E.7.1.1

First administration to humans

E.7.1.2

Bioequivalence study

E.7.1.3

Other

E.7.1.3.1

Other trial type description

E.7.2

Therapeutic exploratory (Phase II)

E.7.3

Therapeutic confirmatory (Phase III)

Yes

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

Yes

E.8.1.3

Single blind

Yes

E.8.1.4

Double blind

E.8.1.5

Parallel group

Yes

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

E.8.2.3

Other

Yes

E.8.2.3.1

Comparator description

Treatment as usual

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.8.4.1

Number of sites anticipated in Member State concerned

E.8.5

The trial involves multiple Member States

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

The end of the trial is defined as 3 months following the last follow-up visit of the last patient randomised, or the time of the last data collection (e.g. during Longer-Term Follow-Up), whichever is later’.

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

E.8.9.2

In all countries concerned by the trial months

E.8.9.2

In all countries concerned by the trial days

F. Population of Trial Subjects

F.1 Age Range

F.1.1

Trial has subjects under 18

F.1.1