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The objective of this prospective, randomized, double-blind, parallel-group, placebo-controlled study is to determine the effectiveness of intranasal oxytocin in subjects suffering from chronic daily headache.
The TI004 and TI005 studies both used a randomized, double-blind, placebo-controlled, parallel-group study design. A protocol-specified interim analysis was performed after completion of the first 40 subjects, resulting in termination of the TI004 study and development of the TI005 protocol, which included the following changes from the TI004 protocol:
The primary outcome measure is the reduction in headache intensity after drug administration; secondary outcome measures are the headache symptoms, nausea, vomiting, photophobia, and phonophobia. Additional secondary outcome measures are intake of rescue medication and patient satisfaction over a period of 24 hours.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Syntocinon® TI-004 protocol | Experimental | Treated group |
|
| Sterile water TI-004 protocol | Placebo Comparator | Placebo group |
|
| Syntocinon® TI-005 protocol | Experimental |
| |
| Sterile water TI-005 protocol | Placebo Comparator |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Syntocinon | Drug | 4 actuations in each nostril for a total dose of 32 IU |
|
| Measure | Description | Time Frame |
|---|---|---|
| Reduction in Headache Intensity | Number (Percentage) of participants with headache improvement defined as a reduction from moderate or severe to mild or absent (4-point categorical scale) | 2 hours after administration of study medication |
| Measure | Description | Time Frame |
|---|---|---|
| Reduction in Headache Intensity | Number (Percentage) of participants with headache improvement defined as a reduction from moderate or severe to mild or absent (4-point categorical scale) | ½, 1, 3 (TI005 study only), 4, 8 (TI005 study only), and 24 hours after administration of study medication |
| Average Headache Intensity |
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Inclusion Criteria:
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Egilius LH Spierings, MD, PhD | Harvard Medical School (HMS and HSDM) | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| MedVadis Research Corporation | Wellesley Hills | Massachusetts | 02481 | United States |
In total 79 subjects were screened, of which five were screen failures in the strict sense of the word and 14 were not randomized because the 6-week treatment period had elapsed.
Subjects recruited at dedicated research center
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| ID | Title | Description |
|---|---|---|
| FG000 | Syntocinon® (Oxytocin) TI-004 Protocol | Self-administered by participants in the upright sitting position with the neck flexed. The pump was primed and one nostril was closed with the finger. The tip of the bottle was inserted into the other nostril at an angle of 60 degrees. One actuation (4 IU) was administered while gently sniffing through that nostril. The tip of the bottle was then inserted into the other nostril for administration of another 4 IU. This procedure was repeated three times with 5-minute intervals (allowing for medication uptake and clearance) for a total dose of 32 IU followed by in-clinic observation for 2 hours post-dose in the TI004 study |
| FG001 | Placebo TI-004 Protocol | Administration of placebo similar to oxytocin arm: 4 actuations in each nostril of sterile water with in-clinic observation for 2 hours post-dose in the TI004 study |
| FG002 | Syntocinon® (Oxytocin) TI-005 Protocol | Self-administered by participants in the upright sitting position with the neck flexed. The pump was primed and one nostril was closed with the finger. The tip of the bottle was inserted into the other nostril at an angle of 60 degrees. One actuation (4 IU) was administered while gently sniffing through that nostril. The tip of the bottle was then inserted into the other nostril for administration of another 4 IU. This procedure was repeated seven times with 5-minute intervals (allowing for medication uptake and clearance) for a total dose of 64 IU followed by 4 hours post-dose in-clinic observation in the TI005 study. |
| FG003 | Placebo TI-005 Protocol | Administration of placebo similar to oxytocin arm: 7 actuations of sterile with 5-minute intervals followed by 4 hours post-dose of in-clinic observation in the TI005 study. |
| Title | Milestones | Reasons Not Completed | ||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| TI-004 Protocol |
| |||||||||||||
| TI-005 Protocol |
|
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| ID | Title | Description |
|---|---|---|
| BG000 | Syntocinon® (Oxytocin) TI-004 Protocol | 32 IU intranasally |
| BG001 | Placebo TI-004 Protocol | Sterile water intranasally |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | Mean |
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | |||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Primary | Reduction in Headache Intensity | Number (Percentage) of participants with headache improvement defined as a reduction from moderate or severe to mild or absent (4-point categorical scale) | Posted | Count of Participants | Participants | 2 hours after administration of study medication |
|
Safety was monitored through the collection of health-status changes and adverse-event occurrences during the 8-week study
AEs were recorded with date of onset and resolution, intensity, and relationship to study medication. The safety analysis was conducted on the intention-to-treat population, including all subjects assigned through randomization to treatment with oxytocin or placebo.
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | Syntocinon® (Oxytocin) TI-004 Protocol | Self-administered by participants in the upright sitting position with the neck flexed. The pump was primed and one nostril was closed with the finger. The tip of the bottle was inserted into the other nostril at an angle of 60 degrees. One actuation (4 IU) was administered while gently sniffing through that nostril. The tip of the bottle was then inserted into the other nostril for administration of another 4 IU. This procedure was repeated three times with 5-minute intervals (allowing for medication uptake and clearance) for a total dose of 32 IU followed by in-clinic observation for 2 hours post-dose in the TI004 study. |
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| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Conjunctivitis | Eye disorders | CTCAE (4.0) | Non-systematic Assessment | Treatment-related adverse event: Assessed by the investigator as possibly or probably causally related to treatment |
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| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Egilius L.H. Spierings, M.D., Ph.D. | MedVadis Research Corporation | 781-588-5430 | Spierings@MedVadis.com |
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| ID | Term |
|---|---|
| D020773 | Headache Disorders |
| ID | Term |
|---|---|
| D001927 | Brain Diseases |
| D002493 | Central Nervous System Diseases |
| D009422 | Nervous System Diseases |
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| ID | Term |
|---|---|
| D010121 | Oxytocin |
| ID | Term |
|---|---|
| D010909 | Pituitary Hormones, Posterior |
| D010907 | Pituitary Hormones |
| D036361 | Peptide Hormones |
| D006728 | Hormones |
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| Sterile water | Drug | 4 actuations in each nostril |
|
|
| Syntocinon | Drug | 8 actuations in each nostril for a total dose of 64 IU |
|
|
| Sterile water | Drug | 8 actuations in each nostril |
|
|
Average headache intensity as rated on the 11-point numerical rating scale (0 = no pain; 10 = worst pain possible). |
| ½, 1, 2, 3 (TI005 study only), 4, 8 (TI005 study only), and 24 hours after administration of study medication |
| Presence of Nausea, Vomiting, Photophobia, and Phonophobia | Number (percentage) of participants with effects of oxytocin on symptoms associated with chronic daily headache, such as nausea, vomiting, photophobia, and phonophobia | ½, 1, 2, 3 (TI005 study only), 4, 8 (TI005 study only), and 24 hours after administration of study medication |
| Intake of Rescue Medication | Number of participants who took rescue medication (examples: ibuprofen, Tylenol, zolmitriptan) for headache at any time within the 24 hours after intervention administration. | Up to 24 hours after intervention administration |
| Participant Satisfaction | Participants rated their satisfaction with treatment on a 4-point scale as "Excellent", "Good", "Moderate", or "Poor". Number (percentage) of participants who reported each rating. | Up to 24 hours after intervention administration |
| COMPLETED |
|
| NOT COMPLETED |
|
| BG002 | Syntocinon® (Oxytocin) TI-005 Protocol | 64 IU intranasally |
| BG003 | Placebo TI-005 Protocol | Sterile water intranasally |
| BG004 | Total | Total of all reporting groups |
| years |
|
| Sex: Female, Male | Count of Participants | Participants |
|
| Ethnicity (NIH/OMB) | Count of Participants | Participants |
|
| Race (NIH/OMB) | Count of Participants | Participants |
|
64 IU intranasally
| OG003 | Placebo TI-005 Protocol | Sterile water intranasally |
|
|
| Secondary | Reduction in Headache Intensity | Number (Percentage) of participants with headache improvement defined as a reduction from moderate or severe to mild or absent (4-point categorical scale) | Number of participants analyzed indicates the number of participants available at each time point. 3 hours and 8 hours were not collected for TI-004 protocol | Posted | Count of Participants | Participants | ½, 1, 3 (TI005 study only), 4, 8 (TI005 study only), and 24 hours after administration of study medication |
|
|
|
| Secondary | Average Headache Intensity | Average headache intensity as rated on the 11-point numerical rating scale (0 = no pain; 10 = worst pain possible). | Number of participants analyzed indicates the number of participants available at each time point. 3 hours and 8 hours were not collected for TI-004 protocol | Posted | Mean | Standard Deviation | score on a scale | ½, 1, 2, 3 (TI005 study only), 4, 8 (TI005 study only), and 24 hours after administration of study medication |
|
|
|
| Secondary | Presence of Nausea, Vomiting, Photophobia, and Phonophobia | Number (percentage) of participants with effects of oxytocin on symptoms associated with chronic daily headache, such as nausea, vomiting, photophobia, and phonophobia | Number of participants analyzed indicates the number of participants available at each time point. 3 hours and 8 hours were not collected for TI-004 protocol | Posted | Count of Participants | Participants | ½, 1, 2, 3 (TI005 study only), 4, 8 (TI005 study only), and 24 hours after administration of study medication |
|
|
|
| Secondary | Intake of Rescue Medication | Number of participants who took rescue medication (examples: ibuprofen, Tylenol, zolmitriptan) for headache at any time within the 24 hours after intervention administration. | All randomized participants | Posted | Count of Participants | Participants | Up to 24 hours after intervention administration |
|
|
|
| Secondary | Participant Satisfaction | Participants rated their satisfaction with treatment on a 4-point scale as "Excellent", "Good", "Moderate", or "Poor". Number (percentage) of participants who reported each rating. | Posted | Count of Participants | Participants | Up to 24 hours after intervention administration |
|
|
|
| 0 |
| 22 |
| 0 |
| 22 |
| 8 |
| 22 |
| EG001 | Sterile Water TI-004 Protocol | Administration of placebo similar to oxytocin arm: 4 actuations in each nostril of sterile water with in-clinic observation for 2 hours post-dose in the TI004 study | 0 | 18 | 0 | 18 | 3 | 18 |
| EG002 | Syntocinon® (Oxytocin) TI-005 Protocol | Self-administered by participants in the upright sitting position with the neck flexed. The pump was primed and one nostril was closed with the finger. The tip of the bottle was inserted into the other nostril at an angle of 60 degrees. One actuation (4 IU) was administered while gently sniffing through that nostril. The tip of the bottle was then inserted into the other nostril for administration of another 4 IU. This procedure was repeated seven times with 5-minute intervals (allowing for medication uptake and clearance) for a total dose of 64 IU followed by 4 hours post-dose in-clinic observation in the TI005 study. | 0 | 12 | 0 | 12 | 2 | 12 |
| EG003 | Sterile Water TI-005 Protocol | Administration of placebo similar to oxytocin arm: 7 actuations of sterile with 5-minute intervals followed by 4 hours post-dose of in-clinic observation in the TI005 study. | 0 | 8 | 0 | 8 | 1 | 8 |
|
| Dry mouth | Gastrointestinal disorders | CTCAE (4.0) | Non-systematic Assessment | Treatment-related adverse event: Assessed by the investigator as possibly or probably causally related to treatment |
|
| Nausea | Gastrointestinal disorders | CTCAE (4.0) | Non-systematic Assessment | NOT Treatment-related adverse event: Assessed by the investigator as not related to treatment |
|
| Rhinitis | Infections and infestations | CTCAE (4.0) | Non-systematic Assessment | Treatment-related adverse event: Assessed by the investigator as possibly or probably causally related to treatment |
|
| Sinusitis | Infections and infestations | CTCAE (4.0) | Non-systematic Assessment | NOT Treatment-related adverse event: Assessed by the investigator as not related to treatment |
|
| Ovarian cyst | Neoplasms benign, malignant and unspecified (incl cysts and polyps) | CTCAE (4.0) | Non-systematic Assessment | NOT Treatment-related adverse event: Assessed by the investigator as not related to treatment |
|
| Dizziness | Nervous system disorders | CTCAE (4.0) | Non-systematic Assessment | Treatment-related adverse event: Assessed by the investigator as possibly or probably causally related to treatment |
|
| Agitation | Nervous system disorders | CTCAE (4.0) | Non-systematic Assessment | Treatment-related adverse event: Assessed by the investigator as possibly or probably causally related to treatment |
|
| Nasal Congestion | Respiratory, thoracic and mediastinal disorders | CTCAE (4.0) | Non-systematic Assessment | Treatment-related adverse event: Assessed by the investigator as possibly or probably causally related to treatment |
|
| Sneezing | Respiratory, thoracic and mediastinal disorders | CTCAE (4.0) | Non-systematic Assessment | Treatment-related adverse event: Assessed by the investigator as possibly or probably causally related to treatment |
|
| Abdominal pain | Gastrointestinal disorders | CTCAE (4.0) | Non-systematic Assessment | Treatment-related adverse event: Assessed by the investigator as possibly or probably causally related to treatment |
|
| Pharyngitis | Infections and infestations | CTCAE (4.0) | Non-systematic Assessment | NOT Treatment-related adverse event: Assessed by the investigator as not related to treatment |
|
| Back pain | Musculoskeletal and connective tissue disorders | CTCAE (4.0) | Non-systematic Assessment | NOT Treatment-related adverse event: Assessed by the investigator as not related to treatment |
|
| Light headedness | Nervous system disorders | CTCAE (4.0) | Non-systematic Assessment | Treatment-related adverse event: Assessed by the investigator as possibly or probably causally related to treatment |
|
| Ankle sprain | Musculoskeletal and connective tissue disorders | CTCAE (4.0) | Non-systematic Assessment | NOT Treatment-related adverse event: Assessed by the investigator as not related to treatment |
|
| Nasal irritation | Respiratory, thoracic and mediastinal disorders | CTCAE (4.0) | Non-systematic Assessment | Treatment-related adverse event: Assessed by the investigator as possibly or probably causally related to treatment |
|
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| D006730 |
| Hormones, Hormone Substitutes, and Hormone Antagonists |
| D010455 | Peptides |
| D000602 | Amino Acids, Peptides, and Proteins |
|
| 1 hour after administration |
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| 3 hours after administration |
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| 4 hours after administration |
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| 8 hours after administration |
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| 24 hours after administration |
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| 1 hour after administration |
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| 2 hours after administration |
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| 3 hours after administration |
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| 4 hours after administration |
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| 8 hours after administration |
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| 24 hours after administration |
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| Nausea at 1 hour |
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| Nausea at 2 hours |
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| Nausea at 3 hours |
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| Nausea at 4 hours |
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| Nausea at 8 hours |
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| Nausea at 24 hours |
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| Vomiting at 0.5 hours |
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| Vomiting at 1 hour |
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| Vomiting at 2 hours |
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| Vomiting at 3 hours |
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| Vomiting at 4 hours |
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| Vomiting at 8 hours |
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| Vomiting at 24 hours |
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| Photophobia at 0.5 hours |
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| Photophobia at 1 hour |
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| Photophobia at 2 hours |
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| Photophobia at 3 hours |
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| Photophobia at 4 hours |
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| Photophobia at 8 hours |
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| Photophobia at 24 hours |
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| Phonophobia at 0.5 hours |
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| Phonophobia at 1 hour |
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| Phonophobia at 2 hours |
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| Phonophobia at 3 hours |
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| Phonophobia at 4 hours |
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| Phonophobia at 8 hours |
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| Phonophobia at 24 hours |
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| "Good" satisfaction rating |
|
| "Moderate" satisfaction rating |
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| "Poor" satisfaction rating |
|
| Satisfaction rating not reported |
|