Phase 1 Pharmacodynamic Study
Conditions
Brief summary
This study is being conducted to assess the plasma CTx-1 concentrations when dosing is at night and to compare these results with those obtained with a placebo control and with commercially available nasal calcitonin.
Detailed description
Timing of the dose of recombinant salmon calcitonin (rsCT) is important in effecting reduction of osteoclast activity. It is theorized that a dose administered before bedtime will be more effective than a dose administered in the morning. See protocol summary for information.
Interventions
DRUGOral rsCT tablet
On Study Day 1, subjects will be given their assigned treatment, based on one of two randomly ordered treatment sequences, at 10 PM (22:00). On Visit 3, subjects will return for administration of the second treatment with a minimum of 7 days washout interval between study drug administrations. On Visit 4, subjects will return for administration of third treatment of rsCT, either oral rsCT tablets or Fortical (rsCT) nasal spray. Interventions are described in Intervention Name, Other Names and in Intervention Description.
Part 1, Double blind oral placebo tablet given once 4 hours after evening meal.
DRUGFortical (rsCT) nasal spray
Intervention: Open label, Fortical nasal spray given once 2 hours after the evening meal.
Sponsors
Tarsa Therapeutics, Inc.
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Caregiver, Investigator)
Eligibility
Sex/Gender
FEMALE
Age
45 Years to 70 Years
Healthy volunteers
Yes
Inclusion criteria
* Postmenopausal female, in good health (at least five years since last menses). * Age greater than or equal to 45 years old and less than or equal to 70 years old * Weight ± 20% of the Metropolitan Life weight table. * Plasma CTx-1 greater than or equal to 0.25 ng/ml. * Total calcium, phosphorus, and magnesium within normal range. * Willing and able to comply with all study requirements. * Willing and able to sign written informed consent. * Negative urine pregnancy test at screening. * Negative Screen for Hepatitis B and C, HIV and drugs of abuse.
Exclusion criteria
* History of parathyroid, thyroid, pituitary or adrenal diseases. * History of musculoskeletal disease. * History of gastro-esophageal reflux disease (GERD) or other significant gastrointestinal disorders. * History of cancer within 5 years of enrollment other than basal cell carcinoma. * History of regular use of a Non-Steroidal Anti-inflammatory Drug (NSAID). * History of surgery within 60 days of enrollment. * History of hypersensitivity or allergies (other than seasonal allergies) within -years of enrollment including known sensitivity to the active ingredients or the excipients in the study medications. * Use of concomitant medications other than acetaminophen within 7 days of enrollment or anticipated need to use such concomitant medications during the study. * Use of bisphosphonates within 6 months, SERMS, estrogen or estrogen-like drugs 2 months, or calcitonin 1 month. * Presence of any clinically significant illness. * Unwilling or unable to comply with all study requirements. * Unwilling or unable to sign written, informed consent. * History of drug or alcohol abuse. * Participation in any clinical study of an investigational drug within 60 days of enrollment. * Plasma CTx-1 less than 0.25 ng/mL.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Pharmacodynamic Effect of Oral Calcitonin | 12 hr | C-terminal telopeptide of Collagen Type I (CTx-1) is an established plasma biomarker employed as an index of bone-resorption activity in response to interventions such as an anti-resorptive agent such as calcitonin. Here the calcitonin-salmon is rsCT, (recombinant) both oral and intranasal. These CTx-1 plasma concentrations were collected over 12 hours post-dosing where each subject served as her own control, as all received placebo in this crossover study, to account for the known diurnal variation of plasma CTx-1. For each time point, the ratio of the calcitonin response over the placebo response for that subject was derived from the plasma levels of CTx-1 and reported as a % of the placebo response (% Placebo or %P). These values were used to determine the primary pharmacodynamic parameter of Rmin, the minimum value seen following each active dose. The same %P values were used to derive the secondary pharmacodynamic parameters described in Secondary outc |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Derived Pharmacodynamic Parameters Further Characterizing the Effects of Oral or Intranasal Calcitonin on Plasma CTx-1, Given at Night to Post-menopausal Women | 12 hours | See Primary Outcome description. These CTx-1 plasma concentrations were collected over 12 hours, the values seen following active were compared with the time-matched individual values following placebo and used to derive the pharmacodynamic parameters. The primary was Rmin, seen above, and the Secondary ones were the time to that Rmin (Tmin) and the total time from the beginning of the inhibition to the end of the effect or the end of the study period (Tinhibition). |
| AUCInhibition=Hours*%P | 12 Hours | The AUCinhibition, (Area Under the Inhibition Curve) in hours\*%inhibition vs placebo under the baseline line over the curve. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Part 1 Oral rsCT Tablets Subjects were given oral rsCT tablets 4 hours after the evening meal | 6 |
| Part 1 Oral Placebo Tablets Subjects were given oral placebo tablets 4 hours after the evening meal. | 6 |
| Part 2 Open Label--Oral rsCT Tablets After completing Part 1, Periods 1 and 2, subjects were eligible to participate in the open label Part 2 (Period 3) when oral rsCT tablets were given 2 hours after the evening meal. | 0 |
| Part 2 Open Label Fortical Intranasal Spray After completing Part 1, Periods 1 and 2, subjects were eligible to participate in the open label Part 2,(Period 3) when they received Fortical intra-nasal spray 2 hours after the evening meal | 0 |
| Total | 12 |
Baseline characteristics
| Characteristic | Part 1 Oral rsCT Tablets | Part 1 Oral Placebo Tablets | Total |
|---|---|---|---|
| Age, Continuous | 59.3 years STANDARD_DEVIATION 4.7 | 59.3 years STANDARD_DEVIATION 4.7 | 59.3 years STANDARD_DEVIATION 4.7 |
| Gender Female | 6 participants | 6 participants | 12 participants |
| Gender Male | 0 participants | 0 participants | 0 participants |
| post-menopausal females | 6 participants | 6 participants | 12 participants |
| post-menopausal healthy females | 6 participants | 6 participants | 12 participants |
| Region of Enrollment United States | 6 participants | 6 participants | 12 participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 1 / 12 | 3 / 12 | 0 / 5 | 1 / 4 |
| serious Total, serious adverse events | 0 / 12 | 0 / 12 | 0 / 5 | 0 / 4 |
Outcome results
Primary
Pharmacodynamic Effect of Oral Calcitonin
C-terminal telopeptide of Collagen Type I (CTx-1) is an established plasma biomarker employed as an index of bone-resorption activity in response to interventions such as an anti-resorptive agent such as calcitonin. Here the calcitonin-salmon is rsCT, (recombinant) both oral and intranasal. These CTx-1 plasma concentrations were collected over 12 hours post-dosing where each subject served as her own control, as all received placebo in this crossover study, to account for the known diurnal variation of plasma CTx-1. For each time point, the ratio of the calcitonin response over the placebo response for that subject was derived from the plasma levels of CTx-1 and reported as a % of the placebo response (% Placebo or %P). These values were used to determine the primary pharmacodynamic parameter of Rmin, the minimum value seen following each active dose. The same %P values were used to derive the secondary pharmacodynamic parameters described in Secondary outc
Time frame: 12 hr
Population: Not applicable. All participants who received treatment were included.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Part 1 Oral rsCT Tablets | Pharmacodynamic Effect of Oral Calcitonin | 37.5 percentage of time-matched placebo respo | Standard Deviation 13.2 |
| Part 1 Oral Placebo Tablets | Pharmacodynamic Effect of Oral Calcitonin | 100 percentage of time-matched placebo respo | — |
| Part 2 Oral rsCT Tablets | Pharmacodynamic Effect of Oral Calcitonin | 41.2 percentage of time-matched placebo respo | Standard Deviation 16.6 |
| Part 2 Fortical Intra-nasal Spray | Pharmacodynamic Effect of Oral Calcitonin | 44.4 percentage of time-matched placebo respo | Standard Deviation 21.8 |
Secondary
AUCInhibition=Hours*%P
The AUCinhibition, (Area Under the Inhibition Curve) in hours\*%inhibition vs placebo under the baseline line over the curve.
Time frame: 12 Hours
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Part 1 Oral rsCT Tablets | AUCInhibition=Hours*%P | 474.7 hours*%P | Standard Deviation 267.7 |
| Part 1 Oral Placebo Tablets | AUCInhibition=Hours*%P | 0 hours*%P | Standard Deviation 0 |
| Part 2 Oral rsCT Tablets | AUCInhibition=Hours*%P | 345.8 hours*%P | Standard Deviation 279 |
| Part 2 Fortical Intra-nasal Spray | AUCInhibition=Hours*%P | 504.7 hours*%P | Standard Deviation 477.4 |
Secondary
Derived Pharmacodynamic Parameters Further Characterizing the Effects of Oral or Intranasal Calcitonin on Plasma CTx-1, Given at Night to Post-menopausal Women
See Primary Outcome description. These CTx-1 plasma concentrations were collected over 12 hours, the values seen following active were compared with the time-matched individual values following placebo and used to derive the pharmacodynamic parameters. The primary was Rmin, seen above, and the Secondary ones were the time to that Rmin (Tmin) and the total time from the beginning of the inhibition to the end of the effect or the end of the study period (Tinhibition).
Time frame: 12 hours
Population: Data from Part 1 (crossover Periods 1 and 2) were pooled to give CTx-1 mean data for the oral rsCT tablet group (n = 12) and for the oral placebo group n = 12). Part 2, open-label, non-crossover, compared the CTx-1 results after oral rsCT (n = 5) with those after Fortical(n = 4. The % inhibition is reported first.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Part 1 Oral rsCT Tablets | Derived Pharmacodynamic Parameters Further Characterizing the Effects of Oral or Intranasal Calcitonin on Plasma CTx-1, Given at Night to Post-menopausal Women | Tmin=time in hours to Rmin | 7.5 Hours | Standard Deviation 5 |
| Part 1 Oral rsCT Tablets | Derived Pharmacodynamic Parameters Further Characterizing the Effects of Oral or Intranasal Calcitonin on Plasma CTx-1, Given at Night to Post-menopausal Women | TInhibition=total time of effect in hours | 10.9 Hours | Standard Deviation 2 |
| Part 1 Oral Placebo Tablets | Derived Pharmacodynamic Parameters Further Characterizing the Effects of Oral or Intranasal Calcitonin on Plasma CTx-1, Given at Night to Post-menopausal Women | TInhibition=total time of effect in hours | 0 Hours | Standard Deviation 0 |
| Part 1 Oral Placebo Tablets | Derived Pharmacodynamic Parameters Further Characterizing the Effects of Oral or Intranasal Calcitonin on Plasma CTx-1, Given at Night to Post-menopausal Women | Tmin=time in hours to Rmin | 0 Hours | Standard Deviation 0 |
| Part 2 Oral rsCT Tablets | Derived Pharmacodynamic Parameters Further Characterizing the Effects of Oral or Intranasal Calcitonin on Plasma CTx-1, Given at Night to Post-menopausal Women | Tmin=time in hours to Rmin | 4.5 Hours | Standard Deviation 5 |
| Part 2 Oral rsCT Tablets | Derived Pharmacodynamic Parameters Further Characterizing the Effects of Oral or Intranasal Calcitonin on Plasma CTx-1, Given at Night to Post-menopausal Women | TInhibition=total time of effect in hours | 9.9 Hours | Standard Deviation 2.6 |
| Part 2 Fortical Intra-nasal Spray | Derived Pharmacodynamic Parameters Further Characterizing the Effects of Oral or Intranasal Calcitonin on Plasma CTx-1, Given at Night to Post-menopausal Women | Tmin=time in hours to Rmin | 4.0 Hours | Standard Deviation 3.5 |
| Part 2 Fortical Intra-nasal Spray | Derived Pharmacodynamic Parameters Further Characterizing the Effects of Oral or Intranasal Calcitonin on Plasma CTx-1, Given at Night to Post-menopausal Women | TInhibition=total time of effect in hours | 10.7 Hours | Standard Deviation 3 |