Stress FracturePhase 3PHABNCT04921124
Pharmacokinetic and PHarmacodynamic Analysis and Evaluation of Teriparatide (PTH 1-34) Between Sexes
A Phase 3 study testing Teriparatide in people with Stress Fracture, run by Norfolk and Norwich University Hospitals NHS Foundation Trust at 1 site in United Kingdom.
Trial summary
To test for a difference in the pharmacokinetics (PK) and pharmacodynamics (PD) of teriparatide (PTH 1-34), between healthy male and female volunteers matched to military recruits in training. Read more about this study
- Who is it for?
- Ages 18 to 36 yearsHealthy volunteers can take part
- Conditions the study is for
- Stress Fracture
- What is being tested?
- Teriparatide
- Type of treatment
- Injection or infusion
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 30 participants
- Where
- 1 siteUnited Kingdom
- Study dates
- 24 May 2021to 9 Jul 2021
- Phase
- Phase 3
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 to 36 years
- All sexes
- Healthy volunteers accepted
- Adult
Who may be able to join
- Have provided written informed consent to participate;
- Be able to comply with protocol;
- Be able to adequately understand written and spoken English;
- Be aged between 18 and 36 years;
- Have a BMI ≥18.5 and ≤28.0 kg/m2;
- Regularly perform a minimum of 3 sessions / week of 40 minutes or more of moderate or vigorous exercise;
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- Be without any clinically significant illness (free from immune, cardiovascular or metabolic diseases and absence of medical conditions that would be a bar to joining the Army),
- Have baseline blood tests within reference range as per screening assessment table (table 1). Minor abnormalities will be assessed by the PI. Participants will still be eligible if these are felt to be of no clinical importance and this decision is documented by the PI;
- Be vitamin D replete (25(OH)D ≥50 nmol/L). Potential participants presenting with 25(OH)D <50 nmol/L I will be offered supplementation and may be re-screened once their course of treatment is complete
Who cannot join
- Hypersensitivity to the active PTH or any of the excipients listed in any of the SmPCs.
- Pre-existing hypercalcaemia
- Participants with skeletal malignancies or bone metastases.
- Significant musculoskeletal injury or fracture within the last 6 months. Significance to be determined by the PI.
- Digoxin and any other concurrent therapy that, in the investigators' opinion, would interfere with the evaluation of the safety or efficacy of the study medication.
- Pregnancy, suspected pregnancy or breastfeeding. Female participants must have a negative urine pregnancy test at screening and be willing and able to use a medically accepted method of birth control (reliable use of oral contraceptive, hormonal intrauterine device, non-hormonal intrauterine device with condom, diaphragm with condom, or condom with spermicide) from the screening visit through to the end of the experimental testing visit or declare that they are abstaining from sexual intercourse from the screening visit through the end of the experimental testing visit or are surgically sterile (have undergone bilateral tubal ligation, bilateral oophorectomy, or hysterectomy).
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- Less than 6 months post-partum.
- Less than 6 months post-breastfeeding.
- Severe renal impairment (eGFR <30mLs/min/1.73m2).
- Pre-existing metabolic bone diseases including hyperparathyroidism and Paget's disease of the bone.
- Unexplained elevations of total ALP.
- Prior external beam or implant radiation therapy to the skeleton.
- Participating in a concurrent drug trial. Potential participants will be excluded if they have been in receipt of an investigational drug or biological agent within the last 4 weeks (or 5 times the half-life if this is longer) prior to study entry.
Trial locations and contacts
1 site in 1 country.
United Kingdom1 site
Norfolk and Norwich University Hospitals Foundation Trust
Norwich, Norfolk, NR4 7UY
About this study
To test for a difference in the pharmacokinetics (PK) and pharmacodynamics (PD) of teriparatide (PTH 1-34), between healthy male and female volunteers matched to military recruits in training.
Read the detailed description
Teriparatide, first licensed for fracture prevention in osteoporosis in 2003, is a human recombinant preparation of parathyroid hormone (PTH) 1-34. The licensed dose is a 20 µg sub-cutaneous (S/C) injection delivered once daily using a pre-filled pen. Published pharmacokinetic (PK) and pharmacodynamic (PD) data focus on administration in adult female pre-menopausal women. Eli Lilly did not publish their original 'First in Human' data, therefore there is a lack of available data in men. The patent on the Eli Lilly formulation expired in August 2019 and three teriparatide biosimilars have been released onto the UK market. Gedeon Richter and Thornton and Ross presented data in osteoporotic patients to the MHRA to license their products as biosimilars. Teriparatide has also been investigated in the treatment of stress fractures, but there are no published data comparing the PKs and PDs of these drugs in a population equivalent to individuals undergoing military training (i.e. young healthy men and women).
Existing data to support the equivalence of teriparatide between sexes is limited. Citrate and calcium infusions have been used to characterise the impact of sex differences on PTH dynamics in twelve women with mean age ± SD of 26.4 ± 1.6 years and 12 men with mean age of 26.6 ± 1.3 years. They reported no between sex differences in serum PTH concentrations. It has also been reported that 2-weeks of intermittent PTH administration in mice was anabolic for cortical bone, with a greater effect observed in male compared with female animals. No studies have investigated between sex PK or PD differences or efficacy of teriparatide injection in humans. By examining this, the present study will help to further our understanding of how teriparatide can be used in men and women.
A review considering a number of trials supported the use of PTH in its licensed indications and demonstrated the efficacy of this drug in both male and female subjects. The evidence base cited in this review is primarily from post-menopausal women in line with the licensed indication.
This study compliments the RETURN trial which is investigating the efficacy of teriparatide for accelerating stress fracture healing in Army infantry recruits (EudraCT: 2018-002130-20). The study is based at the Infantry Training Centre (ITC), which currently predominantly trains men, hence men will form the majority of the RETURN study participants. Opening front line roles to women comes with a well-documented risk of musculoskeletal injury due to the nature of infantry training (HQ Army, 2016). If the results of the RETURN trial are to be extrapolated to women and inform Defence treatment policy for stress fractures, the between sex differences in PK and PD in a population matched to individuals in military training must be established. This study is required if the results of RETURN are to be extrapolated to a female population undergoing military training.
The Gedeon Richter preparation, 'Terossa' will be used in this study as this is the preparation that is being used in the RETURN study. This will control for inter-brand variation.
Nephrogenous cyclic Adenosine Mono Phosphate is a measurement of PTH 1-34 activity at the kidney and can therefore be used to estimate the early biological effects of PTH 1-34 in humans.
The research questions are;
- Is there a difference in the PK or PD profile of teriparatide subcutaneous injection between men and women?
- Are the PK and PD measurements reliable and reproducible? The cohort for investigation is young healthy (free from immune, cardiovascular or metabolic diseases) men and women, military or physically trained civilians, free from illness, and matched to a military population in training, based on age, body mass index (BMI) and absence of medical conditions that would be a bar to entry to the Army (Can I Join The Army | Find Out if You Are Eligible | British Army - British Army Jobs (mod.uk) [Accessed 16/01/2021]).
The intervention involves a single dose of teriparatide administered on 2 occasions.
Participants will be closely monitored for 12 hours, plus a further 12 hours urine collection followed by a 24-hour washout period.
- Conditions
- Stress Fracture
- Being tested
- Teriparatide
- Medical subject headings
- Fractures, Stress
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
TeriparatideDrug
PTH(1-34) cartridge and pen device
| Study group | Role | What they receive |
|---|---|---|
| Treatment | Experimental | Teriparatide, 20 µg Subcutaneous (S/C) per day.
Two doses in total. Receives: Drug: Teriparatide |
What is being measured
The primary outcome is the main question the study is designed to answer.
Concentration over time assessed by the area under the curve (AUC) of teriparatide (PTH (1-34)).
Compared in men and women.
Measured: One dose (24 hours)
The maximum concentration (Cmax) for teriparatide (PTH 1-34).
Compared in men and women.
Measured: One dose (24 hours)
Secondary outcomes (5)
Changes in cAMP production over time following a single dose of teriparatide.
Compared in men and women.
Measured: One dose (24 hours)
Changes in cAMP metabolism over time following a single dose of teriparatide.
Compared in men and women.
Measured: One dose (24 hours)
The reproducibility of Concentration over time assessed by the area under the curve (AUC) of teriparatide (PTH (1-34)).
Compared in men and women.
Measured: Two doses (24 hours wash out between )
The reproducibility of changes in cAMP production over time following a repeated dose of teriparatide.
Compared in men and women.
Measured: Two doses (24 hours wash out between )
The reproducibility of changes in cAMP metabolism over time following a repeated dose of teriparatide.
Compared in men and women.
Measured: Two doses (24 hours wash out between )
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted10 Jun 2021
- Study start24 May 2021
- Primary completion5 Jul 2021
- Study completion9 Jul 2021
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Other trials for Stress FractureStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 3
- Primary purpose
- Other
- Allocation
- Not applicable
- Intervention model
- Single group
- Model description
- This is an open-label, parallel, clinical trial in two separate groups, men and women.
- Masking
- None (open label)
- Enrolment
- 30 participants (actual)
Sponsor and investigators
- Lead sponsor
- Norfolk and Norwich University Hospitals NHS Foundation Trust
- Sponsor type
- University, hospital or other
- Collaborators
- University of East Anglia, Ministry of Defence, United Kingdom
- Responsible party
- Sponsor
- Investigators
- William Fraser, Prof, Principal investigator, UEA
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT04921124
- Sponsor's protocol ID
- PHAB01
- Acronym
- PHAB
- Status last verified
- Aug 2021
- First submitted
- 19 May 2021
- Last updated
- 12 Aug 2021
- Results posted
- No
- Data monitoring committee
- No
- FDA-regulated drug
- No
- FDA-regulated device
- No
- Individual data sharing
- No
Study at a glance
From the registry record, last updated by the sponsor on 12 Aug 2021. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Pharmacokinetic and PHarmacodynamic Analysis and Evaluation of Teriparatide (PTH 1-34) Between Sexes
- ClinicalTrials.gov ID
- NCT04921124
- Acronym / sponsor ID
- PHAB / PHAB01
- Conditions
- Stress Fracture
- Phase
- Phase 3
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 30 participants (actual)
- Lead sponsor
- Norfolk and Norwich University Hospitals NHS Foundation TrustUniversity, hospital or other
- Collaborators
- University of East Anglia, Ministry of Defence, United Kingdom
- Study start
- 24 May 2021 (actual)
- Primary completion
- 5 Jul 2021 (actual)
- Study completion
- 9 Jul 2021 (actual)
- First posted
- 10 Jun 2021 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
To test for a difference in the pharmacokinetics (PK) and pharmacodynamics (PD) of teriparatide (PTH 1-34), between healthy male and female volunteers matched to military recruits in training.
Detailed description
Teriparatide, first licensed for fracture prevention in osteoporosis in 2003, is a human recombinant preparation of parathyroid hormone (PTH) 1-34. The licensed dose is a 20 µg sub-cutaneous (S/C) injection delivered once daily using a pre-filled pen. Published pharmacokinetic (PK) and pharmacodynamic (PD) data focus on administration in adult female pre-menopausal women. Eli Lilly did not publish their original 'First in Human' data, therefore there is a lack of available data in men. The patent on the Eli Lilly formulation expired in August 2019 and three teriparatide biosimilars have been released onto the UK market. Gedeon Richter and Thornton and Ross presented data in osteoporotic patients to the MHRA to license their products as biosimilars. Teriparatide has also been investigated in the treatment of stress fractures, but there are no published data comparing the PKs and PDs of these drugs in a population equivalent to individuals undergoing military training (i.e. young healthy men and women).
Existing data to support the equivalence of teriparatide between sexes is limited. Citrate and calcium infusions have been used to characterise the impact of sex differences on PTH dynamics in twelve women with mean age ± SD of 26.4 ± 1.6 years and 12 men with mean age of 26.6 ± 1.3 years. They reported no between sex differences in serum PTH concentrations. It has also been reported that 2-weeks of intermittent PTH administration in mice was anabolic for cortical bone, with a greater effect observed in male compared with female animals. No studies have investigated between sex PK or PD differences or efficacy of teriparatide injection in humans. By examining this, the present study will help to further our understanding of how teriparatide can be used in men and women.
A review considering a number of trials supported the use of PTH in its licensed indications and demonstrated the efficacy of this drug in both male and female subjects. The evidence base cited in this review is primarily from post-menopausal women in line with the licensed indication.
This study compliments the RETURN trial which is investigating the efficacy of teriparatide for accelerating stress fracture healing in Army infantry recruits (EudraCT: 2018-002130-20). The study is based at the Infantry Training Centre (ITC), which currently predominantly trains men, hence men will form the majority of the RETURN study participants. Opening front line roles to women comes with a well-documented risk of musculoskeletal injury due to the nature of infantry training (HQ Army, 2016). If the results of the RETURN trial are to be extrapolated to women and inform Defence treatment policy for stress fractures, the between sex differences in PK and PD in a population matched to individuals in military training must be established. This study is required if the results of RETURN are to be extrapolated to a female population undergoing military training.
The Gedeon Richter preparation, 'Terossa' will be used in this study as this is the preparation that is being used in the RETURN study. This will control for inter-brand variation.
Nephrogenous cyclic Adenosine Mono Phosphate is a measurement of PTH 1-34 activity at the kidney and can therefore be used to estimate the early biological effects of PTH 1-34 in humans.
The research questions are;
- Is there a difference in the PK or PD profile of teriparatide subcutaneous injection between men and women?
- Are the PK and PD measurements reliable and reproducible? The cohort for investigation is young healthy (free from immune, cardiovascular or metabolic diseases) men and women, military or physically trained civilians, free from illness, and matched to a military population in training, based on age, body mass index (BMI) and absence of medical conditions that would be a bar to entry to the Army (Can I Join The Army | Find Out if You Are Eligible | British Army - British Army Jobs (mod.uk) [Accessed 16/01/2021]).
The intervention involves a single dose of teriparatide administered on 2 occasions.
Participants will be closely monitored for 12 hours, plus a further 12 hours urine collection followed by a 24-hour washout period.
Study design
- Primary purpose
- Other
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Number of arms
- 1
- Model description
- This is an open-label, parallel, clinical trial in two separate groups, men and women.
| Arm | Type | Receives |
|---|---|---|
| Treatment | Experimental | Drug: TeriparatideTeriparatide, 20 µg Subcutaneous (S/C) per day. Two doses in total. |
Who may qualify
- Ages
- 18 to 36 years
- Sex
- All
- Healthy volunteers
- Accepted
- Age groups
- Adult
Key inclusion criteria (9 listed)
- Have provided written informed consent to participate;
- Be able to comply with protocol;
- Be able to adequately understand written and spoken English;
- Be aged between 18 and 36 years;
- Have a BMI ≥18.5 and ≤28.0 kg/m2;
Key exclusion criteria (13 listed)
- Hypersensitivity to the active PTH or any of the excipients listed in any of the SmPCs.
- Pre-existing hypercalcaemia
- Participants with skeletal malignancies or bone metastases.
- Significant musculoskeletal injury or fracture within the last 6 months. Significance to be determined by the PI.
- Digoxin and any other concurrent therapy that, in the investigators' opinion, would interfere with the evaluation of the safety or efficacy of the study medication.
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| TeriparatidePTH(1-34) cartridge and pen device | Drug | Treatment |
Primary outcome
Concentration over time assessed by the area under the curve (AUC) of teriparatide (PTH (1-34)).
Time frame: One dose (24 hours)
Compared in men and women.
The maximum concentration (Cmax) for teriparatide (PTH 1-34).
Time frame: One dose (24 hours)
Compared in men and women.
5 secondary outcomes
Changes in cAMP production over time following a single dose of teriparatide.
Time frame: One dose (24 hours)
Changes in cAMP metabolism over time following a single dose of teriparatide.
Time frame: One dose (24 hours)
The reproducibility of Concentration over time assessed by the area under the curve (AUC) of teriparatide (PTH (1-34)).
Time frame: Two doses (24 hours wash out between )
The reproducibility of changes in cAMP production over time following a repeated dose of teriparatide.
Time frame: Two doses (24 hours wash out between )
The reproducibility of changes in cAMP metabolism over time following a repeated dose of teriparatide.
Time frame: Two doses (24 hours wash out between )
Results and safety
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 12 Aug 2021.
- Individual participant dataSharing planned: No
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
William Fraser, Prof principal investigator
UEA
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 3 study testing Teriparatide in people with Stress Fracture, run by Norfolk and Norwich University Hospitals NHS Foundation Trust at 1 site in United Kingdom.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 9 inclusion and 13 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 12 Aug 2021. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in United Kingdom. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 3 studies compare the treatment with the current standard treatment or a placebo in a large group, to confirm how well it works and watch for side effects.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Concentration over time assessed by the area under the curve (AUC) of teriparatide (PTH (1-34)). (time frame: One dose (24 hours)). The study lists 2 primary outcomes in all. It is what the study was designed to measure, not a finding.
Where can I read the original study information?
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 12 Aug 2021.